This application is a 371 of PCT/JP99/06764 filed Dec. 2, 1999.
The present invention relates to novel benzofuran derivatives, their production, and pharmaceutical compositions containing them. More specifically, it relates to compounds having excellent pharmacological activities such as a neurotrophic factor-like activity, a neurotrophic factor activity-enhancing activity, a neurodegeneration inhibitory activity, a xcex2-amyloid toxicity inhibitory activity and the like, and are effective as prophylactic and therapeutic drugs for neurodegenerative diseases and the like.
Neurodegenerative diseases are progressive diseases to cause destructive injuries such as the nerve cell death. As principal neurodegenerative diseases, there have been known central nervous diseases such as Alzheimer""s disease, Parkinson""s disease, amyotrophic lateral sclerosis (ALS), Hantington""s disease, and the like and peripheral neuropathies such as typically diabetic neuropathy. Many of them relate to aging and, in fact, the onset increases with aging, whereas there is a case in which the onset begins even at a middle age and further at a younger age.
As a result of studies on the structure and function of brains, the roles of neurotransmitters and neurotrophic factors and so on have been gradually elucidated, but many parts of the causes of neurodegeneration are still unknown. Only for Parkinson""s disease, the relation between it and a specific neurotransmitter, namely dopamine, has been clarified, whereby L-dopa that is the precursor of dopamine has been used as a drug for reducing the nervous symptoms and for recovering the function. However, L-dopa does not suppress the progress of neurodegeneration, and the effect of L-dopa is gradually lost with a progress of the disease condition, namely the degeneration and deficiency of dopamine-based nerve cells. Also, Alzheimer""s disease is a disease that is caused by the degeneration and deficiency of a variety of nerve cells such as acetylcholine-based nerve cells, monoamine-based nerve cells, and the like and, as for the drugs therefor, cholinesterase inhibitors have been marketed or under development. Nevertheless, like L-dopa for Parkinson""s disease, they are still within the region of symptomatic therapy to improve the nerve symptoms temporarily.
Thus, there has not been reported up to the present time any drug that protects nerve cells from the toxicity of factors causing cell death thereby suppressing the progress of neurodegenerative diseases including Alzheimer""s disease and Parkinson""s disease.
Moreover, it is said that the cell death in neurodegenerative diseases is caused by the toxicity of the factors that are intrinsic to the respective diseases and, for example, in Alzheimer""s disease, the endogenous xcex2-amyloid is considered to be a factor to cause the cell death. xcex2-Amyloid is a protein constituting the senile plaque, which is a neuropathological characteristic to be seen in brain of a patient suffering from Alzheimer""s disease, and is composed of 40 to 43 amino acids. It has been elucidated that the addition of this xcex2-amyloid to a primary culture of hippocampus nerve cell causes nerve cell death [Science, Vol. 245, pp. 417-420 (1989)] and, also, it has been shown that the coagulation of xcex2-amyloid is indispensable for the expression of its toxicity and the like [Neurobiology of Aging, Vol. 13, pp. 587-590 (1992) and Journal of Molecular Biology, Vol. 218, pp. 149-163 (1991)]. For toxicity expression mechanism of xcex2-amyloid, there have been conceived that 1) xcex2-amyloid forms an ion channel to allow an inflow of calcium ions, 2) xcex2-amyloid accelerates generation of free radicals, 3) xcex2-amyloid activates tau protein kinase I (TPK-I) to promote the phosphorylation of tau, 4) xcex2-amyloid activates the microglia, from which the neurotoxin is secreted, and the like.
Recently, it has been elucidated that neurotrophic factors such as IGF-1 (insulin-like growth factor), NGF (nerve growth factor), and the like inhibit the apoptosis of nerve cells by xcex2-amyloid and the like, and that, as the mechanism thereof, inhibition of TPK-I/GSK-3xcex2 (glycogen synthetase kinase 3) by activation of PI-3 kinase is concerned in the apoptosis inhibition [Journal of Neuroscience (J. Neurosci.), Vol. 11, pp. 2552-2563 (1991), Science, Vol. 267, pp. 2003-2005 (1995), and The Journal of Biological Chemistry (J. Biol. Chem.), Vol. 272, 154-161 (1997)]. When PI-3 kinase is inhibited by xcex2-amyloid and TPK-I/GSK-3xcex2 is activated, pyruvate dehydrogenase (PDH) is inhibited, thereby affecting the synthetic reaction system of acetylcholine to lower the content of acetylcholine. This fact agrees with an observation that the content of acetylcholine is lowered in brain of a patient suffering from Alzheimer""s disease. On the contrary, it is expected that the activation of PI-3 kinase results in not only the prevention of nerve cell death but also an increase in the content of acetylcholine in brain, thereby improving the nerve symptoms. In addition, it can be expected that inhibition of TPK-I/GSK-3xcex2 increases the intracerebral glucose utilization, which is lowered in Alzheimer""s disease [The Journal of Biological Chemistry (J. Biol. Chem.), Vol. 269, 3568-3573 (1994) and Endocrinology, Vol. 125, pp. 314-320 (1989)].
Further, the following compounds have been reported as compounds having a fused nitrogen-containing heterocyclic group on benzene ring that is fuzed with furan ring or dihydrofuran ring.
1) As compounds having an inhibitory activity of bone resorption and bone metabolism, compounds that are represented by the formula: 
wherein R1 is hydrogen, lower alkyl, acyl, amino, acylamino, nitro, halogen or hydroxy-lower alkyl that may have one or more appropriate substituents;
R2 is hydrogen, lower alkyl, acyl, lower alkoxy, acyl-lower alkyl, aryl, cyano, mono- (or di- or tri-) halo-lower alkyl, lower alkylthio or hydroxy-lower alkyl that may have one or more appropriate substituents;
R3 is hydrogen, lower alkyl, lower alkenyl, cyclo lower alkyl-lower alkyl, halogen, acyl, acyl-lower alkyl, acylamino, acylamino-lower alkyl, acyl-lower alkenyl, acyloxy-lower alkyl, acyl-lower alkylthio-lower alkyl, amino-lower alkyl, mono- (or di-) lower alkylamino, lower alkylthio-lower alkyl, hydroxyimino-lower alkyl that may have one or more appropriate substituents, hydroxy-lower alkyl that may have one or more appropriate substituents, hydroxy-lower alkylthio-lower alkyl, cyano-lower alkyl, mono- (or di-) lower alkoxyower alkyl that may have one or more appropriate substituents, lower alkyl substituted with aryl that may have one or more appropriate substituents, mono- (or di-) lower alkylamino-lower alkyl, lower alkyl substituted with a heterocyclic group that may have one or more appropriate substituents, a heterocyclic group that may have one or more appropriate substituents, heterocyclic thio, heterocyclic thio-lower alkyl, heterocyclic oxy, heterocyclic oxy-lower alkyl, heterocyclic aminoimino-lower alkyl, aryl, amino or nitro;
R2 and R3 may be combined each other to form a group of
(1) lower alkylene that may have one or more appropriate substituents,
(2) lower alkenylene that may have one or more appropriate substituents, or
(3) the formula: xe2x80x94(A1)mxe2x80x94Wxe2x80x94(A2)nxe2x80x94, wherein each of A1 and A2 is lower alkylene that may have one or more appropriate substituents or lower alkenylene that may have one or more appropriate substituents, W is xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94 or xe2x80x94N(R5)xe2x80x94 (wherein R5 is hydrogen, lower alkyl or acyl), and each of m and n is an integer of 0 or 1;
X is O or S, Y is vinylene or a group represented by the formula: xe2x80x94NHCOxe2x80x94, xe2x80x94NHSO2xe2x80x94, xe2x80x94OCOxe2x80x94, xe2x80x94OCH2xe2x80x94, xe2x80x94NHCOCOxe2x80x94, xe2x80x94NHCOCHxe2x95x90CHxe2x80x94, xe2x80x94NHCOCH2xe2x80x94, xe2x80x94NHCONHxe2x80x94 or xe2x80x94N(R6)COxe2x80x94 (wherein R6 is lower alkyl); Z is a heterocyclic group that may have one or more appropriate substituents or aryl that may have one or more appropriate substituents; 1 is an integer of 0 or 1; and --- represents a single bond or a double bond, and pharmaceutically acceptable salts thereof, and specifically, 
(WO 95/29907 and JP 9-512795 A).
2) As compounds having an inhibitory activity of lipid peroxide formation, 3,5-dihydroxyheptanoic acid derivatives represented by the formula: 
wherein R1 is hydrogen, nitro, a group represented by xe2x80x94N(R4)R5, wherein each of R4 and R5 is hydrogen, lower alkyl, lower alkenyl, aryl, aralkyl, acyl, aroyl, substituted or unsubstituted carbamoyl or substituted or unsubstituted thiocarbamoyl, or R4 and R5 together may form cyclic amino; each of R2 and R3 is hydrogen or lower alkyl], and 3,5-dihydroxyheptanoic acid derivatives represented by the formula: 
wherein R1 is hydrogen, nitro, a group represented by xe2x80x94N(R4)R5, wherein each of R4 and R5 is hydrogen, lower alkyl, lower alkenyl, aryl, aralkyl, acyl, aroyl, substituted or unsubstituted carbamoyl or substituted or unsubstituted thiocarbamoyl group, or R4 and R5 together may form cyclic amino; each of R2 and R3 is hydrogen or lower alkyl; R6 is hydrogen, lower alkyl, alkali metal or alkaline earth metal (JP 5-194466 A).
3) As herbicides, compounds represented by the formula: 
wherein R is H, Cl, F, C1-C2 alkyl or C1-C2 alkoxy; R, is H, F, Cl, Br, CH3, OCH3, CN, CF3, OCF3 or OCF2H; X1 is O; R2 is H, CH3 or CH2CH3; R3 is H, C1-C4 haloalkyl, CR2R7CN, CN, CR2R4R7, COCl, COR4, C(NOR6)R2, C2R4, CONR4R2, CHR2OH, CO2(CH2)2Si (CH3)3, CONR2SO2CH3, CHR2CO2R4, CONHCH(CH3)CONHCH(CH3)CO2CH3, CHR2COR4, CHR2OSO2(C1-C4 alkyl), CHR2OC(O)R4, CHR2OC(O)N(R2)2, CHR2OC(O)N(R2)OCH3, CHR2OC(O)N(R2)Ph, HCxe2x95x90CH2 or Cxe2x89xa1CH; R4 is H, C1-C4 alkyl, C1-C4 haloalkyl, C2-C6 alkenyl, C3-C6 alkynyl, C2-C4 haloalkenyl, phenyl, C1-C4 alkylphenyl, C3-C6 alkoxycarbonylalkyl or (CH2CH2O)bR2; b is 1 to 6; m is 1, n is 1 or 2; J is 
(wherein X and Y are O or S, respectively), etc. (U.S. Pat. No. 4,881,967)
4) As compounds having an antibacterial activity, compounds represented by the formula: 
wherein each of m and n is 0 or 1 and the sum of m and n is 1; R is hydrogen or lower alkyl; Rxe2x80x2 is R, 
or R and Rxe2x80x2 together form (CH3)2Nxe2x80x94Nxe2x95x90, 
or form pyrrole or pyrrolidine; Rxe2x80x3 is R, lower alkyl, CF3xe2x80x94, or ClCH2xe2x80x94; and Rxe2x80x2xe2x80x3 is lower alkyl or CF3xe2x80x94, or pharmacologically acceptable salts thereof (U.S. Pat. No. 4,212,865).
5) compound that is a synthetic intermediate and is represented by the formula: 
[Tetrahedron Letters, Vol. 37, No. 51, pp. 9183-9186 (1996)].
6) As compounds having an inhibitory activity of lipid peroxide formation, compounds represented by the formula: 
wherein R1 and R2 are the same or different and each is hydrogen, acyl, alkoxycarbonyl, or an aliphatic or aromatic group which respectively may be substituted; R3, R4, and R5 are the same or different and each is hydroxyl that may be acylated, or amino, alkoxy or an aliphatic group, which respectively may be substituted, or two of R3, R4, and R5 may form a carbon homocyclic ring that may be substituted;
R6 and R7 are the same or different and each is an aliphatic group that may be substituted, and at least one of R6 and R7 has methylene at the xcex1 position; and R8 and R9 are the same or different and each is hydrogen, or an aliphatic or aromatic group, which respectively may be substituted, or salts thereof (EP-A-483772 and JP 5-140142 A).
7) As compounds having bone resorption inhibitory activity, compounds represented by the formula: 
wherein R1 is formyl, carbamoyl-lower alkyl, thiomorpholinocarbonyl-lower alkyl, thiomorpholinocarbonyl-lower alkyl S-oxide, pyridylaminocarbonyl-lower alkyl, pyrazolylaminocarbonyl-lower alkyl, triazolylaminocarbonyl-lower alkyl, quinolylaminocarbonyl-lower alkyl that may have one or more appropriate substituents, 3-pyridyl-lower alkylaminocarbonyl-lower alkyl, 4-pyridyl-lower alkylaminocarbonyl-lower alkyl, pyridylethylaminocarbonyl-lower alkyl, pyridyl-lower alkylaminocarbonyl-lower alkyl N-oxide, benzimidazolyl-lower alkylaminocarbonyl-lower alkyl, N-pyridyl-lower alkyl-N-acyl-lower alkylaminocarbonyl-lower alkyl, N-pyridyl-N-lower alkylaminocarbonyl-lower alkyl, lower alkylaminocarbonyl-lower alkyl, di-lower alkylaminocarbonylmethyl, quinolyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl, cyano-lower alkyl, di-lower alkylamino-lower alkyl, pyridyl-lower alkyl, triazolyl-lower alkyl, pyrazolyl-lower alkyl that may have one or more appropriate substituents, pyrimidinyl-lower alkyl that may have one or more appropriate substituents, dihydrophthalazinyl-lower alkyl that may have one or more appropriate substituents, oxadiazolyl-lower alkyl that may have one or more appropriate substituents, heterocyclic-lower alkenyl that may have one or more appropriate substituents, lower alkoxyower alkylamino-lower alkyl that may have one or more appropriate substituents, aryl-lower alkylaminocarbonyl-lower alkyl that may have one or more appropriate substituents, arylaminocarbonyl-lower alkyl that may have one or more appropriate substituents, arylthio-lower alkyl that may have one or more appropriate substituents, lower alkyl or an imidazolyl-lower alkyl;
R2 is lower alkyl, protected carboxyl or cyano; R3 is halogen or lower alkyl; R4 is hydrogen, nitro or amino; and
R5 is halogen, lower alkyl or nitro; provided that, 1) when R1 is methyl, R2 is protected carboxyl or cyano and, 2) when R1 is imidazolylmethyl, R2 is protected carboxyl or cyano, or salts thereof (JP 9-124633 A).
8) As compounds having sodium channel regulating activity, compounds represented by the formula: 
wherein each of R1 and R2 is hydrogen atom, lower alkyl that may be substituted or acyl;
each of R3, R4 and R5 is lower alkyl that may be substituted or lower alkoxy that may be substituted, or R4 and R5 together may form a 5- or 6-membered homocyclic ring;
R6 is lower alkyl;
Ar is an aromatic group that may be substituted;
ring A is a 5- to 8-membered nitrogen-containing heterocyclic ring that may be substituted;
X is a lower alkylene that may have substituents;
Y is carbon atom or nitrogen atom;
Za is a group represented by CH2, COCH(R7), OCH(R7), SCH(R7), or N(R10)CH(R7) (wherein R7 is hydrogen atom or an aromatic group that may be substituted; and R10 is hydrogen, a hydrocarbon group that may be substituted, or acyl); Zb is a bivalent aliphatic hydrocarbon group which may have a binding bond or a substituent and may be bonded through oxygen atom, nitrogen atom or sulfur atom; and m is an integer of 1 to 3, or salts thereof (WO 98/08842).
Low-molecular weight compounds, which are excellent in intracerebral permeability and have a neurotrophic factor-like activity and a neurotrophic factor-enhancing activity, are considered to be capable of inhibiting nerve cell death in neurodegenerative diseases such as Alzheimer""s disease and the like as well as of improving the symptoms. Then, it has been desired to develop compounds which have a neurotrophic factor-like activity and/or a neurotrophic factor-enhancing activity and, furthermore have excellent pharmacological activities such as a protecting activity of nerve cells by inhibiting cytotoxicity of xcex2-amyloid, or a protecting activity of nerve cells from toxicity of a factor causing nerve cell death, and the like, thereby being useful for pharmaceuticals such as prophylactic and therapeutic drugs of neurodegenerative diseases, and the like.
As a result of intensive studies, the present inventors have synthesized for the first time novel compounds represented by the formula: 
wherein R1 and R2 are the same or different and each is hydrogen atom, a hydrocarbon group that may be substituted or a heterocyclic group that may be substituted, or R1 and R2 may form, together with the adjacent carbon atom, a 3- to 8-membered homocyclic or heterocyclic ring that may be substituted;
R3a is hydrogen atom, a hydrocarbon group that may be substituted or a heterocyclic group that may be substituted;
--- is a single bond or a double bond;
ring A is benzene ring that may be substituted;
ring B is a 5- to 7-membered nitrogen-containing heterocyclic ring which may be substituted with halogen or a hydrocarbon group that may be substituted,
ring C1 is benzene ring which may be substituted with halogen, lower alkyl that may be halogenated, lower alkoxy that may be halogenated and lower alkylthio that may be halogenated, in addition to the group represented by the formula: 
xe2x80x83(wherein each symbol is as defined above), or salts thereof [hereinafter, sometimes, abbreviated as compounds (Ia)]. These compounds have a chemical structural characteristic in that the benzene ring condensed with the furan or dihydrofuran ring is substituted with the group represented by the formula: 
(each symbol is as defined above).
Further, unexpectedly, the present inventors have found that the compounds (Ia) have, on the basis of the specific chemical structure thereof, excellent pharmacological activities such as a neurotrophic factor-like activity, a neurotrophic factor enhancing activity, an inhibitory activity of cytotoxicity of xcex2-amyloid, etc. The present inventors have also found that compounds including compounds (Ia) and represented by the formula: 
wherein R1 and R2 are the same or different and each is hydrogen atom, a hydrocarbon group that may be substituted or a heterocyclic group that may be substituted, or R1 and R2 may form, together with the adjacent carbon atom, a 3- to 8-membered homocyclic or heterocyclic ring that may be substituted;
R3a is hydrogen atom, a hydrocarbon group that may be substituted or a heterocyclic group that may be substituted;
--- is a single bond or a double bond;
ring A is benzene ring that may be substituted;
ring Ba indicates a 5- to 7-membered heterocyclic ring that may be substituted;
ring Ca is benzene ring that may be substituted in addition to the group represented by the formula: 
xe2x80x83(wherein each symbol is as defined above), or salts thereof [hereinafter, sometimes, abbreviated as compounds (Iaxe2x80x2)] have, on the basis of the specific chemical structure of the substituent on ring Ca, 
xe2x80x83a neurotrophic factor-like activity, a neurotrophic factor enhancing activity, an inhibitory activity of cytotoxicity of xcex2-amyloid, etc. and, further that these compounds (Ia) and compounds (Iaxe2x80x2) have extremely low toxicity, are excellent in the brain penetrability and have an inhibitory activity of neurodegeneration, etc., thereby being fully satisfactory as pharmaceuticals.
Moreover, the present inventors have synthesized for the first time novel compounds represented by the formula: 
wherein R1 and R2 are the same or different and each is hydrogen atom, a hydrocarbon group that may be substituted or a heterocyclic group that may be substituted, or R1 and R2 may form, together with the adjacent carbon atom, a 3- to 8-membered homocyclic or heterocyclic ring that may be substituted;
R3b is C6-14 aryl that may be substituted;
R4 is (1) an aliphatic hydrocarbon group which may be substituted with an aromatic group that may be substituted and, further, may be substituted, or (2) acyl containing an aromatic group that may be substituted;
R5 is hydrogen atom, C1-6 alkyl or acyl;
--- indicates a single bond or a double bond;
ring C2 is benzene ring that may be substituted in addition to a group represented by formula xe2x80x94NR4(R5) (wherein each symbol is as defined above), or salts thereof [hereinafter, sometimes, abbreviated as compounds (Ib)]. These compounds have a chemical structural characteristic in that the benzene ring condensed with the furan or dihydrofuran ring is substituted with the group represented by formula xe2x80x94NR4(R5) (wherein R4 is a group containing aromatic ring) and, further, the benzofuran or dihydrofuran ring is substituted with an aryl group at the 3-position thereof.
Unexpectedly, the present inventors have further found that the thus-obtained compounds (Ib) have, on the basis of the specific chemical structure thereof, excellent pharmaceutical activities such as a neurotrophic factor-like activity, a neurotrophic factor enhancing activity, an inhibitory activity of cytotoxicity of xcex2-amyloid, etc. and, further that these compounds have extremely low toxicity, are excellent in the brain penetrability and have an inhibitory activity of neurodegeneration, etc., thereby being fully satisfactory as pharmaceuticals.
The present inventors have further studied on the basis of these findings. As a result, the present invention has been completed. That is, the present invention provides:
1. A compound represented by the formula: 
xe2x80x83wherein R1 and R2 are the same or different and each is hydrogen atom, a hydrocarbon group that may be substituted or a heterocyclic group that may be substituted, or R1 and R2 may form, together with the adjacent carbon atom, a 3- to 8-membered homocyclic or heterocyclic ring that may be substituted; --- is a single bond or a double bond;
W is
(i) a group represented by the formula: 
xe2x80x83wherein ring A is benzene ring that may be substituted and ring B is a 5- to 7-membered nitrogen-containing heterocyclic ring which may be substituted with halogen or a hydrocarbon group that may be substituted, or
(ii) a group represented by the formula: 
xe2x80x83wherein R4 is (1) an aliphatic hydrocarbon group which is substituted with an aromatic group that may be substituted and, said, may further be substituted or (2) an acyl group containing an aromatic group that may be substituted; R5 is hydrogen atom, a C1-6 alkyl group, or an acyl group] and, when W is Wa, R3 is hydrogen atom, a hydrocarbon group that may be substituted, or a heterocyclic group that may be substituted and ring C is benzene ring that may be substituted with substituent(s) selected from halogen, lower alkyl that may be halogenated, lower alkoxy that may be halogenated and lower alkylthio that may be halogenated, in addition to the group represented by Wa, and, when W is Wb, R3 is a C6-14 aryl group that may be substituted and ring C is benzene ring that may further be substituted, in addition to the group represented by Wb, provided that, when --- is a double bond, the partial structure: 
xe2x80x83or a salt thereof;
2. A compound represented by the formula: 
xe2x80x83wherein R1 and R2 are the same or different and each is hydrogen atom, a hydrocarbon group that may be substituted or a heterocyclic group that may be substituted, or R1 and R2 may form, together with the adjacent carbon atom, a 3- to 8-membered homocyclic or heterocyclic ring that may be substituted;
R3a is hydrogen atom, a hydrocarbon group that may be substituted or a heterocyclic group that may be substituted;
--- is a single bond or a double bond;
ring A is benzene ring that may be substituted,
ring B is a 5- to 7-membered nitrogen containing heterocyclic ring which may be substituted with halogen or a hydrocarbon group that may be substituted;
ring C1 is benzene ring that may further be substituted with a substituent selected from halogen, lower alkyl that may be halogenated, lower alkoxy that may be halogenated and lower alkylthio that may be halogenated, in addition to the group represented by the formula: 
xe2x80x83(wherein each symbol is as defined above), provided that, when --- is a double bond, the partial structure: 
xe2x80x83or a salt thereof;
3. A compound represented by the formula: 
xe2x80x83wherein R1 and R2 are the same or different and each is hydrogen atom, a hydrocarbon group that may be substituted or a heterocyclic group that may be substituted, or R1 and R2 may form, together with the adjacent carbon atom, a 3- to 8-membered homocyclic or heterocyclic ring that may be substituted;
R3b is a C6-14 aryl group that may be substituted;
R4 is (1) an aliphatic! hydrocarbon group which is substituted with an aromatic group that may be substituted and, may further be substituted, or (2) an acyl group containing an aromatic group that may be substituted;
R5 is hydrogen atom, a C1-6 alkyl group, or an acyl group;
--- is a single bond or a double bond;
ring C2 is benzene ring that may further be substituted, in addition to the group represented by xe2x80x94NR4(R5) (each symbol is as defined above),
provided that, when --- is a double bond, the partial structure: 
xe2x80x83or a salt thereof;
4. The compound according to the above 1, wherein R1 and R2 are the same or different and each is (i) hydrogen atom, (ii) a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-6 cycloalkyl group, or a C6-14 aryl group, which respectively may have 1 to 5 substituents selected from (1) halogen, (2) C1-3 alkylenedioxy, (3) nitro, (4) cyano, (5) C1-6 alkyl that may be halogenated, (6) C2-6 alkenyl that may be halogenated, (7) C2-6 alkynyl that may be halogenated, (8) C3-6 cycloalkyl that may be halogenated, (9) C6-14 aryl, (10) C1-6 alkoxy that may be halogenated, (11) C1-6 alkylthio that may be halogenated or mercapto, (12) hydroxyl, (13) amino, (14) mono-C1-6 alkylamino, (15) mono-C6-14 arylamino, (16) di-C1-6 alkylamino, (17) di-C6-14 arylamino, (18) acyl selected from formyl, carboxyl, carbamoyl, C1-6 alkyl-carbonyl, C3-6 cycloalkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-14 aryl-carbonyl, C7-16 aralkyl-carbonyl, C6-14 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl containing, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-14 aryl-carbamoyl, thiocarbamoyl, 5- or 6-membered heterocyclic carbamoyl containing, in addition to carbon atom(s), 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, C1-6 alkylsulfonyl, C6-14 arylsulfonyl, C1-6 alkylsulfinyl, and C6-14 arylsulfinyl, (19) acylamino selected from formylamino, C1-6 alkyl-carboxamido, C6-14 aryl-carboxamido, C1-6 alkoxy-carboxamido, C1-6 alkylsulfonylamino, and C6-14 arylsulfonylamino, (20) acyloxy selected from C1-6 alkyl-carbonyloxy, C6-14 aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-6 alkyl-carbamoyloxy, C6-14 aryl-carbamoyloxy and nicotinoyloxy, (21) 5- to 7-membered saturated cyclic amino, which may have 1 to 3 substituents selected from C1-6 alkyl, C6-14 aryl, and 5- to 10-membered aromatic heterocyclic group containing, in addition to carbon atom(s), 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, (22) 5- to 10-membered aromatic heterocyclic group containing, in addition to 1carbon atom(s), 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, (23) sulfo, and (24) C6-14 aryloxy, or
(iii) 5- to 14-membered heterocyclic group containing, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, which respectively may have 1 to 5 substituents selected from (1) halogen, (2) C1-3 alkylenedioxy, (3) nitro, (4) cyano, (5) C1-6 alkyl that may be halogenated, (6) C2-6 alkenyl that may be halogenated, (7) C2-6 alkynyl that may be halogenated, (8) C3-6 cycloalkyl that may be halogenated, (9) C6-14 aryl, (10) C1-6 alkoxy that may be halogenated, (11) C1-6 alkylthio that may be halogenated or mercapto, (12) hydroxyl, (13) amino, (14) mono-C1-6 alkylamino, (15) mono-C6-14 arylamino, (16) di-C1-6 alkylamino, (17) di-C6-14 arylamino, (18) acyl selected from formyl, carboxyl, carbamoyl, C1-6 alkyl-carbonyl, C3-6 cycloalkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-14 aryl-carbonyl, C7-16 aralkyl-carbonyl, C6-14 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl containing, in addition to carbon atom(s), 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-14 aryl-carbamoyl, thiocarbamoyl, 5- or 6-membered heterocyclic carbamoyl containing, in addition to carbon atom(s), 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, C1-6 alkylsulfonyl, C6-14 arylsulfonyl, C1-6 alkylsulfinyl and C6-14 arylsulfinyl, (19) acylamino selected from formylamino, C1-6 alkyl-carbonylamino, C6-14 aryl-carbonylamino, C1-6 alkoxy-carbonylamino, C1-6 alkylsulfonylamino and C6-14 arylsulfonylamino, (20) acyloxy selected from C1-6 alkyl-carbonyloxy, C6-14 aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-6 alkyl-carbamoyloxy, C6-14 aryl-carbamoyloxy and nicotinoyloxy, (21) 5- to 7-membered saturated cyclic amino, which may have 1 to 3 substituents selected from C1-6 alkyl, C6-14 aryl and 5- to 10-membered aromatic heterocyclic group containing, in addition to carbon atom(s), 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, (22) 5- to 10-membered aromatic heterocyclic group containing, in addition to carbon atom(s), 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, (23) sulfo, and (24) a C6-14 aryloxy, or
(iv) R1 and R2 form, together with the adjacent carbon atom, C3-8 cycloalkane or a 3- to 8-membered heterocyclic ring containing, in addition to carbon atom(s), 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, which respectively may have 1 to 5 substituents selected from (1) halogen, (2) C1-3 alkylenedioxy, (3) nitro, (4) cyano, (5) C1-6 alkyl that may be halogenated, (6) C2-6 alkenyl that may be halogenated, (7) C2-6 alkynyl that may be halogenated, (8) C3-6 cycloalkyl that may be halogenated, (9) C6-14 aryl, (10) C1-6 alkoxy that may be halogenated, (11) C1-6 alkylthio that may be halogenated or mercapto, (12) hydroxyl, (13) amino, (14) mono-C1-6 alkylamino, (15) mono-C6-14 arylamino, (16) di-C1-6 alkylamino, (17) di-C6-14 arylamino, (18) acyl selected from formyl, carboxyl, carbamoyl, C1-6 alkyl-carbonyl, C3-6 cycloalkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-14 aryl-carbonyl, C7-16 aralkyl-carbonyl, C6-14 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl containing, in addition to carbon atom, 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom, and oxygen atom, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, thiocarbamoyl, C6-14 aryl-carbamoyl, 5- or 6-membered heterocyclic carbamoyl containing, in addition to carbon atom, 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom, C1-6 alkylsulfonyl, C6-14, arylsulfonyl, C1-6 alkylsulfinyl, and C6-14 arylsulfinyl, (19) acylamino selected from formylamino, C1-6 alkylcarbonylamino, C6-14 arylcarbonylamino, C1-6 alkoxycarbonylamino, C1-6 alkylsulfonylamino, and C6-14 arylsulfonylamino, (20) acyloxy selected from C1-6 alkylcarbonyloxy, C6-14 arylcarbonyloxy, C1-6 alkoxycarbonyloxy, mono-C1-6 alkylcarbamoyloxy, di-C1-6 alkylcarbamoyloxy, C6-14 arylcarbamoyloxy and nicotinoyloxy, (21) 5- to 7-membered saturated-cyclic amino, which may have 1 to 3 substituents selected from a C1-6 alkyl, C6-14 aryl, and a 5- to 10-membered aromatic heterocyclic group containing, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, (22) a 5- to 10-membered aromatic heterocyclic group containing, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom, and oxygen atom, (23) sulfo, and (24) C6-14 aryloxy;
(i) when W is Wa,
R3 is (i) hydrogen atom, (ii) a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-6 cycloalkyl group or a C6-14 aryl group which respectively may have 1 to 5 substituents selected from (1) halogen, (2) C1-3 alkylenedioxy, (3) nitro, (4) cyano, (5) C1-6 alkyl that may be halogenated, (6) C2-6 alkenyl that may be halogenated, (7) C2-6 alkynyl that may be halogenated, (8) C3-6 cycloalkyl that may be halogenated, (9) C6-14 aryl, (10) C1-6 alkoxy that may be halogenated, (11) C1-6 alkylthio that may be halogenated or mercapto, (12) hydroxyl, (13) amino, (14) mono-C1-6 alkylamino, (15) mono-C6-14 arylamino, (16) di-C1-6 alkylamino, (17) di-C6-14 arylamino, (18) acyl selected from formyl, carboxyl, carbamoyl, C1-6 alkyl-carbonyl, C3-6 cycloalkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-14 aryl-carbonyl, C7-16 aralkyl-carbonyl, C6-14 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl containing, in addition to carbon atom, 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-14 aryl-carbamoyl, thiocarbamoyl, 5- or 6-membered, heterocyclic carbamoyl containing, in addition to carbon atom, 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom, C1-6 alkylsulfonyl, C6-14 arylsulfonyl, C1-6 alkylsulfinyl and C6-14 arylsulfinyl, (19) acylamino selected from formylamino, C1-6 alkyl-carboxamido, C6-14 aryl-carboxamido, C1-6 alkoxy-carboxamido, C1-6 alkylsulfonylamino and C6-14 arylsulfonylamino, (20) acyloxy selected from C1-6 alkyl-carbonyloxy, C6-14 aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, a mono-C1-6 alkyl-carbamoyloxy, a di-C1-6 alkyl-carbamoyloxy, C6-14 aryl-carbamoyloxy and nicotinoyloxy, (21) 5- to 7-membered saturated-cyclic amino, which may have 1 to 3 substituents selected from C1-6 alkyl, C6-14 aryl, and a 5- to 10-membered aromatic heterocyclic group containing, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, (22) a 5- to 10-membered aromatic heterocyclic group containing, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, (23) sulfo, and (24) C6-14 aryloxy; or
(iii) a 5- to 14-membered heterocyclic group containng, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, which may have 1 to 5 substituents selected from (1) halogen, (2) C1-3 alkylenedioxy, (3) nitro, (4) cyano, (5) C1-6 alkyl that may be halogenated, (6) C2-6 alkenyl that may be halogenated, (7) C2-6 alkynyl that may be halogenated, (8) C3-6 cycloalkyl that may be halogenated, (9) C6-14 aryl, (10) C1-6 alkoxy that may be halogenated, (11) C1-6 alkylthio that may be halogenated or mercapto, (12) hydroxyl, (13) amino, (14) mono-C1-6 alkylamino, (15) mono-C6-14 arylamino, (16) di-C1-6 alkylamino, (17) di-C6-14 arylamino, (18) acyl selected from formyl, carboxyl, carbamoyl, C1-6 alkyl-carbonyl, C3-6 cycloalkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-14 aryl-carbonyl, C7-16 aralkyl-carbonyl, C6-14 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-1, aryl-carbamoyl, thiocarbamoyl, 5- or 6-membered heterocyclic carbamoyl that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom an d oxygen atom, C1-6 alkylsulfonyl, C6-14 arylsulfonyl, C1-6 alkylsulfinyl and C6-14 arylsulfinyl, (19) acylamino selected from formylamino, C1-6 alkyl-carbonylamino, C6-14 aryl-carbonylamino, C1-6 alkoxy-carbonylamino, C1-6 alkylsulfonylamino and C6-14 arylsulfonylamino, (20) acyloxy selected from C1-6 alkyl-carbonyloxy, C6-14 aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-6 alkyl-carbamoyloxy, C6-14 aryl-carbamoyloxy and nicotinoyloxy, (21) 5- to 7-membered saturated-cyclic amino, which may have 1 to 3 substituents selected from C1-6 alkyl, C6-14 aryl, and a 5- to 10-membered aromatic heterocyclic group that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, (22) a 5- to 10-membered aromatic heterocyclic group that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, (23) sulfo, and (24) a C6-14 aryloxy;
ring A is benzene ring, which respectively may have 1 to 5 substituents selected from (1) halogen, (2) C1-3 alkylenedioxy, (3) nitro, (4) cyano, (5) C1-6 alkyl that may be halogenated, (6) C2-6 alkenyl that may be halogenated, (7) C2-6 alkynyl that may be halogenated, (8) C3-6 cycloalkyl that may be halogenated, (9) C6-14 aryl, (10) C1-6 alkoxy that may be halogenated, (11) C1-6 alkylthio that may be halogenated or mercapto, (12) hydroxyl, (13) amino, (14) mono-C1-6 alkylamino, (15) mono-C6-14 arylamino, (16) di-C1-6 alkylamino, (17). di-C6-14 arylamino, (18) acyl selected from formyl, carboxyl, carbamoyl, C1-6 alkyl-carbonyl, C3-6 cycloalkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-14 aryl-carbonyl, C7-16 aralkyl-carbonyl, C6-14 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-14 aryl-carbamoyl, thiocarbamoyl, 5- or 6-membered, heterocyclic carbamoyl that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, C1-6 alkylsulfonyl, C6-14 arylsulfonyl, C1-6 alkylsulfinyl and C6-14 arylsulfinyl, (19) acylamino selected from formylamino, C1-6 alkylcarboxamido, C6-14 arylcarboxamido, C1-6 alkoxycarboxamido, C1-6 alkylsulfonylamino and C6-14 arylsulfonylamino, (20) acyloxy selected from C1-6 alkyl-carbonyloxy, C6-14 aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-6 alkyl-carbamoyloxy, C6-14 aryl-carbamoyloxy, and nicotinoyloxy, (21) 5- to 7-membered saturated-cyclic amino, which may have 1 to 3 substituents selected from C1-6 alkyl, C6-14 aryl and a 5- to 10-membered aromatic heterocyclic group that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, (22) a 5- to 10-membered aromatic heterocyclic group that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, (23) sulfo, and (24) a C6-14 aryloxy;
ring B is a 5- to 7-membered nitrogen-containing heterocyclic ring that may be substituted with (i) halogen or (ii) a C1-6 alkyl group, a C26 alkenyl group, a C26 alkynyl group, a C3-6 cycloalkyl group, or a C6-14 aryl group, which respectively may have 1 to 5 substituents selected from (1) halogen, (2) C1-3 alkylenedioxy, (3) nitro, (4) cyano, (5) C1-6 alkyl that may be halogenated, (6) C2-6 alkenyl that may be halogenated, (7) C2-6 alkynyl that may be halogenated, (8) C3-6 cycloalkyl that may be halogenated, (9) C6-14 aryl, (10) C1-6 alkoxy that may be halogenated, (11) C1-6 alkylthio that may be halogenated or mercapto, (12) hydroxyl, (13) amino, (14) mono-C1-6 alkylamino, (15) mono-C6-14 arylamino, (16) di-C1-6 alkylamino, (17) di-C6-14 arylamino, (18) acyl selected from formyl, carboxyl, carbamoyl, C1-6 alkyl-carbonyl, C3-6 cycloalkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-14 aryl-carbonyl, C7-16 aralkyl-carbonyl, C6-14 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-14 aryl-carbamoyl, thiocarbamoyl, 5- or 6-membered heterocyclic carbamoyl that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, C1-6 alkylsulfonyl, C6-14 arylsulfonyl, C1-6 alkylsulfinyl and C6-14 arylsulfinyl, (19) acylamino selected from formylamino, C1-6 alkyl-carboxamido, C6-14 aryl-carboxamido, C1-6 alkoxy-carboxamido, C1-6 alkylsulfonylamino and C6-14 arylsulfonylamino, (20) acyloxy selected from C1-6 alkyl-carbonyloxy, C6-14 aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-6 alkyl-carbamoyloxy, C6-14 aryl-carbamoyloxy, and nicotinoyloxy, (21) 5- to 7-membered saturated-cyclic amino, which may have 1 to 3 substituents selected from C1-6 alkyl, C6-14 aryl, and a 5- to 10-membered aromatic heterocyclic group that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, (22) a 5- to 10-membered aromatic heterocyclic group that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, (23) sulfo, and (24) a C6-14 aryloxy; and
ring C is benzene ring that may be substituted with a substituent selected from halogen, C1-6 alkyl that may be halogenated, C1-6 alkoxy that may be halogenated, and C1-6 alkylthio that may be halogenated in addition to the group represented by the formula: 
(ii) when W is Wb,
R3 is C6-14 aryl, which respectively may have 1 to 5 substituents selected from (1) halogen, (2) C1-3 alkylenedioxy, (3) nitro, (4) cyano, (5) C1-6 alkyl that may be halogenated, (6) C2-6 alkenyl that may be halogenated, (7) C2-6 alkynyl that may be halogenated, (8) C3-6 cycloalkyl that may be halogenated, (9) C6-14 aryl, (10) C1-6 alkoxy that may be halogenated, (11) C1-6 alkylthio that may be halogenated or mercapto, (12) hydroxyl, (13) amino, (14) mono-C1-6 alkylamino, (15) mono-C6-14 arylamino, (16) di-C1-6 alkylamino, (17) di-C6-14 arylamino, (18) acyl selected from formyl, carboxyl, carbamoyl, C1-6 alkyl-carbonyl, C3-6 cycloalkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-14 aryl-carbonyl, C7-16 aralkyl-carbonyl, C6-14 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-14 aryl-carbamoyl, thiocarbamoyl, 5- or 6-membered heterocyclic carbamoyl that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, C1-6 alkylsulfonyl, C6-14 arylsulfonyl, C1-6 alkylsulfinyl and C6-14 arylsulfinyl, (19) acylamino selected from formylamino, C1-6 alkyl-carbonylamino, C6-14 aryl-carbonylamino, C1-6 alkoxy-carbonylamino, C1-6 alkylsulfonylamino and C6-14 arylsulfonylamino, (20) acyloxy selected from C1-6 alkyl-carbonyloxy, C6-14 aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-6 alkyl-carbamoyloxy, C6-14 aryl-carbamoyloxy and nicotinoyloxy, (21) 5- to 7-membered saturated-cyclic amino, which may have 1 to 3 substituents selected from C1-6 alkyl, C6-14 aryl and a 5- to 10-membered aromatic heterocyclic group that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, (22) a 5- to 10-membered aromatic heterocyclic group that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, (23) sulfo, and (24) a C6-14 aryloxy;
R4 is (i) a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, or a C3-6 has 1 to 3 groups of a C6-14 aryl group and a 5- to 14-membered, aromatic heterocyclic group that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, which respectively may have 1 to 5 substituents selected from (1) halogen, (2) C1-3 alkylenedioxy, (3) nitro, (4) cyano, (5) C1-6 alkyl that may be halogenated, (6) C2-6, alkenyl that may be halogenated, (7) C2-6 alkynyl that may be halogenated, (8) C3-6 cycloalkyl that may be halogenated (9) C6-14 aryl, (10) C1-6, alkoxy that may be halogenated, (11) C1-6 alkylthio that may be halogenated or mercapto, (12) hydroxyl, (13) amino, (14) mono-C1-6 alkylamino, (15) mono-C6-14 arylamino, (16) di-C1-6 alkylamino, (17) di-C6-14 arylamino, (18) acyl selected from formyl, carboxyl, carbamoyl, C1-6 alkyl-carbonyl, C3-6 cycloalkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-14 aryl-carbonyl, C7-16 alkyl-carbonyl, C6-14 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-14 aryl-carbamoyl, thiocarbamoyl, 5- or 6-membered heterocyclic carbamoyl that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, C6-14 alkylsulfonyl, C6-14 arylsulfonyl, C1-6 alkylsulfinyl and C6-14 arylsulfinyl, (19) acylamino selected from formylamino, C1-6 alkylcarbonylamino, C6-14 aryl-carbonylamino, C1-6 alkoxycarbonylamino, C1-6 alkylsulfonylamino and C6-14 arylsulfonylamino, (20) acyloxy selected from C1-6alkylcarbonyloxy, C6-14 aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-6 alkyl-carbamoyloxy, C6-14 aryl-carbamoyloxy and nicotinoyloxy, (21) 5- to 7-membered saturated-cyclic amino, which may have 1 to 3 substituents selected from C1-6alkyl, C6-14 aryl, and a 5- to 10-membered aromatic heterocyclic group that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, (22) a 5- to 10-membered aromatic heterocyclic group that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, (23) sulfo, and (24) a C6-14 aryloxy, and further may have 1 to 5 substituents selected from (1) halogen, (2) C3-6 alkylenedioxy, (3) nitro, (4cyano (5) C1-6 alkyl that may be halogenated, (6) C2-6 alkenyl that may be halogenated, (7) C2-6 alkynyl that may be halogenated, (8) C3-6 cycloalkyl that may be halogenated, (9) C6-14 aryl, (10) C1-6 alkoxy that may be halogenated, (11) C1-6 alkylthio that may be halogenated or mercapto, (12) hydroxyl, (13) amino, (14) mono-C1-6 alkylamino, (15) mono-C6-14 arylamino, (16) di-C1 6 alkylamino, (17) di-C6-14 arylamino, (18) acyl selected from formyl, carboxyl, carbamoyl, C1-6 alkyl-carbonyl, C3-6 cycloalkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-14 aryl-carbonyl, C7-16 aralkyl-carbonyl, C6-14 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-14 aryl-carbamoyl, thiocarbamoyl, 5- or 6-membered heterocyclic carbamoyl that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, C1-6alkylsulfonyl, C6-14 arylsulfonyl, C1-6 alkylsulfinyl, and C6-14 arylsulfinyl, (19) acylamino selected from formylamino, C1-6 alkyl-carbonylamino, C6-14 aryl-carbonylamino, C1-6 alkoxy-carbonylamino, C1-6 alkylsulfonylamino and C6-14 arylsulfonylamino, (20) acyloxy selected from C1-6 alkylcarbonyloxy, C6-14 aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-6 alkyl-carbamoyloxy, C6-14 aryl-carbamoyloxy and nicotinoyloxy, (21) 5- to 7-membered saturated-cyclic amino which may have 1 to 3 substituents selected from C1-6 alkyl, C6-14 aryl and 5- to 10-membered aromatic heterocyclic group that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, (22) a 5- to 10-membered, aromatic heterocyclic group that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, (23) sulfo, and (24) a C6-14 aryloxy, or
(ii) an acyl group that is selected from formyl, carboxyl, carbamoyl, C1-6 alkyl-carbonyl, C3-6 cycloalkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-14 aryl-carbonyl, C7-16 aralkyl-carbonyl, C6-14 aryl-oxycarbonyl, C7-16 aralkyl-oxycarbonyl, 5- or 6-membered heterocyclic carbonyl that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom, and oxygen atom, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-14 aryl-carbamoyl, thiocarbamoyl, 5- or 6-membered heterocyclic carbamoyl that contains, in addition to carbon atom, 1 to 4 hetero atom selected from nitrogen atom, sulfur atom and oxygen atom, C1-6 alkylsulfonyl, C6-14 arylsulfonyl, C1-6 alkylsulfinyl and C6-14 arylsulfinyl,
which has 1 to 3 groups of a C6-14 aryl group and a 5- to 14-membered aromatic heterocyclic group that contains, in addition to the carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, which respectively may have 1 to 5 substituents selected from (1) halogen, (2) C1-3 alkylenedioxy, (3) nitro, (4) cyano, (5) C1-6 alkyl that may be halogenated, (6) C2-6 alkenyl that may be halogenated, (7) C2-6 alkynyl that may be halogenated, (8) C3-6 cycloalkyl that may be halogenated, (9) C6-14 aryl, (10) C1-6 alkoxy that may be halogenated, (11) C1-6 alkylthio that may be halogenated or mercapto, (12) hydroxyl, (13) amino, (14) mono-C1-6 alkylamino, (15) mono-C6-14 arylamino, (16) di-C1-6 alkylamino, (17) di-C6-14 arylamino, (18) acyl selected from formyl, carboxyl, carbamoyl, C1-6 alkyl-carbonyl, C3-6 cycloalkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-14 aryl-carbonyl, C7-16 aralkyl-carbonyl, C6-14 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-14 aryl-carbamoyl, thiocarbamoyl, 5- or 6-membered heterocyclic carbamoyl that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, C1-6 alkylsulfonyl, C6-14 arylsulfonyl, C1-6 alkylsulfinyl and C6-14 arylsulfinyl, (19) acylamino selected from formylamino, C1-6 alkyl-carbonylamino, C6-14 arylcarbonyl-amino, C1-6 alkoxy-carbonylamino, C1-6 alkylsulfonylamino and C6-14 arylsulfonylamino, (20) acyloxy selected from C1-6 alkyl-carbonyloxy, C6-14 aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-6 alkyl-carbamoyloxy, C6-14 aryl-carbamoyloxy, and nicotinoyloxy, (21) 5- to 7-membered saturated-cyclic amino, which may have 1 to 3 substituents selected from C1-6 alkyl, C6-14 aryl, and a 5- to 10-membered, aromatic heterocyclic group that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, (22) a 5- to 10-membered aromatic heterocyclic group that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, (23) sulfo, and (24) C6-14 aryloxy;
R5 is (i) hydrogen atom, (ii) a C1-6 alkyl group, or (iii) acyl selected from formyl, carboxyl, carbamoyl, C1-6 alkyl-carbonyl, C3-6 cycloalkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-14 aryl-carbonyl, C7-16 aralkyl-carbonyl, C6-14 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-14 aryl-carbamoyl, thiocarbamoyl, 5- or 6-membered heterocyclic carbamoyl that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, C1-6 alkylsulfonyl, C6-14 arylsulfonyl, C1-6 alkylsulfinyl and C6-14 arylsulfinyl; and ring C is, in addition to a group represented by the formula xe2x80x94NR4(R5), benzene ring, which may have 1 to 3 substituents selected from (1) halogen, (2) C1-3 alkylenedioxy, (3) nitro, (4) cyano, (5) C1-6 alkyl that may be halogenated, (6) C2-6 alkenyl that may be halogenated, (7) C2-6 alkynyl that may be halogenated, (8) C3-6 cycloalkyl that may be halogenated, (9) C6-14 aryl, (10) C1-6 alkoxy that may be halogenated, (11) hydroxyl, (12) amino, (13) mono-C1-6 alkylamino, (14) mono-C6-14 arylamino, (15) di-C1-6 alkylamino, (16) di-C6-14 arylamino, (17) acyl selected from formyl, carboxyl, carbamoyl, C1-6 alkyl-carbonyl, C3-6 cycloalkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-14 aryl-carbonyl, C7-16 aralkyl-carbonyl, C6-14 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-14 aryl-carbamoyl, thiocarbamoyl, 5- or 6-membered heterocyclic carbamoyl that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, C1-6 alkylsulfonyl, C6-14 arylsulfonyl, C1-6 alkylsulfinyl, and C6-14 arylsulfinyl, (18) acylamino selected from formylamino, C1-6 alkyl-carboxamido, C6-14 aryl-carboxamido, C1-6 alkoxy-carboxamido, C1-6 alkylsulfonylamino and C6-14 arylsulfonylamino, (19) 5- to 7-membered saturated-cyclic amino, which may have 1 to 3 substituents selected from C1-6 alkyl, C6-14 aryl and a 5- to 10-membered aromatic heterocyclic group that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, (20) a 5- to 10-membered aromatic heterocyclic group that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, and (21) sulfo;
5. The compound according to the above 2, wherein R1 and R2 are the same or different and each is hydrogen atom or a C1-6 alkyl group that may have substituents, or R1 and R2 may form, together with the adjacent carbon atom, a 3- to 8-membered heterocyclic ring that may be substituted;
6. The compound according to the above 2, wherein each of R1 and R2is a C1-6 alkyl group;
7. The compound according to the above 2, wherein R3a is a C6-14 aryl group that may be substituted;
8. The compound according to the above 2, wherein R3a is phenyl group that may have C1-6 alkyl or halogen;
9. The compound according to the above 2, wherein ring A is benzene ring that may be substituted selected from halogen, C1-6 alkyl, C1-6 alkoxy, and C1-6 alkylenedioxy;
10. The compound according to the above 2, wherein ring B is a 5- to 7-membered nitrogen-containing heterocyclic ring that may be substituted with C1-6 alkyl;
11. The compound according to the above 2, wherein ring C1 is benzene ring that may be further substituted with C1-6 alkyl or C1-6 alkoxy;
12. The compound according to the above 2, wherein a group represented by the formula: 
xe2x80x83(wherein each symbol is as defined in the above 2) is a group represented by the formula: 
xe2x80x83(wherein R6 and R7 are the same or different and each is hydrogen atom, halogen, or a hydrocarbon group that may be substituted and ring A is as defined in the above 2);
13. The compound according to the above 2, wherein a group represented by the formula: 
xe2x80x83(wherein each symbol is as defined in the above 2) is a group represented by the formula: 
xe2x80x83(wherein R6 and R7 are the same or different and each is hydrogen atom, halogen, or hydrocarbon group that may be substituted and ring A is as defined in the above 2);
14. The compound according to the above 12 or 13, wherein R6 and R7 are hydrogen atoms and ring A is benzene ring that may have 1 or 2 substituents selected from halogen, C1-6 alkoxy, and C1-6 alkylenedioxy;
15. The compound according to the above 2, wherein the substitution position on ring C1 of a group represented by the formula: 
xe2x80x83(wherein each symbol is as defined in the above 2) is 5-position on the benzofuran ring or the dihydrobenzofuran ring;
16. The compound according to the above 2, wherein each of R1 and R2 is a C1-6 alkyl group, R3a is phenyl group that may have C1-6 alkyl or halogen, ring A is benzene ring that may be substituted selected from halogen, C1-6 alkyl, C1-6 alkoxy and C1-6 alkylenedioxy, ring B is a 5- to 7-membered nitrogen-containing heterocyclic ring that may be substituted with C1-6 alkyl, ring C1 is benzene ring that may be further substituted with C1-6 alkyl or C1-6 alkoxy, and a group represented by the formula: 
xe2x80x83(wherein each symbol is as defined in the above 2) is a group represented by the formula: 
xe2x80x83(wherein ring A1 is benzene ring that may have 1 or 2 substituents selected from halogen, C1-6 alkoxy and C1-6 alkylenedioxy);
17. [1] 2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindoline, [2] 5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindoline, [3] 5,6-dimethoxy-2-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]isoindoline, [4] 6-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]-6,7-dihydro-5H-[1,3]dioxolo[4,5-f]isoindole, [5] 6-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]-6H-[1,3]dioxolo[4,5-f]isoindole, [6] 6-[2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl]-6,7-dihydro-5H-[1,3]dioxolo[4,5-f]isoindole, [7] (+)-5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindoline, or [8] (+)-5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindoline hydrochloride;
18. The compound according to the above 3, wherein ring A is benzene ring, which may have 1 to 3 substituents selected from halogen, C1-3 alkylenedioxy, nitro, cyano, C1-6 alkyl that may be halogenated, C2-6 alkenyl that may be halogenated, C2-6 alkynyl that may be halogenated, C3-6 cycloalkyl that may be halogenated, C6-14 aryl, C1-6 alkoxy that may be halogenated, hydroxyl, amino, mono-C1-6 alkylamino, mono-C6-14 arylamino, di-C1-6 alkylamino, di-C6-14 arylamino, acyl, acylamino, 5- to 7-membered saturated-cyclic amino that may be substituted, a 5- to 10-membered aromatic heterocyclic group and sulfo;
19. The compound according to the above 3, wherein R1 and R2 are the same or different and each is (i) hydrogen atom, (ii) a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-6 cycloalkyl group, or a C6-14 aryl group, which respectively may have 1 to 5 substituents selected from (1) halogen, (2) C1-3 alkylenedioxy, (3) nitro, (4) cyano, (5) C1-6 alkyl that may be halogenated, (6) C2-6 alkenyl that may be halogenated, (7) C2-6 alkynyl that may be halogenated, (8) C3-6 cycloalkyl that may be halogenated, (9) C6-14 aryl, (10) C1-6 alkoxy that may be halogenated, (11) C1-6 alkylthio that may be halogenated or mercapto, (12) hydroxyl, (13) amino, (14) mono-C1-6 alkylamino, (15) mono-C6-14 arylamino, (16) di-C1-6 alkylamino, (17) di-C6-14 arylamino, (18) acyl selected from formyl, carboxyl, carbamoyl, C1-6 alkyl-carbonyl, C3-6 cycloalkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-14 aryl-carbonyl, C7-16 aralkyl-carbonyl, C6-14 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-14 aryl-carbamoyl, thiocarbamoyl, 5- or 6-membered heterocyclic carbamoyl that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, C1-6 alkylsulfonyl, C6-14 arylsulfonyl, C1-6 alkylsulfinyl and C6-14 arylsulfinyl, (19) acylamino selected from formylamino, C1-6 alkyl-carboxamido, C6-14 aryl-carboxamido, C1-6 alkoxy-carboxamido, C1-6 alkylsulfonylamino and C6-14 arylsulfonylamino, (20) acyloxy selected from C1-6 alkyl-carbonyloxy, C6-14 aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-6 alkyl-carbamoyloxy, C6-14 aryl-carbamoyloxy and nicotinoyloxy, (21) 5- to 7-membered saturated-cyclic amino, which may have 1 to 3 substituents selected from C1-6 alkyl, C6-14 aryl, and a 5- to 10-membered aromatic heterocyclic group that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, (22) a 5- to 10-membered aromatic heterocyclic group that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, (23) sulfo, and (24) a C6-14 aryloxy, or
(iii) a 5- to 14-membered heterocyclic group that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, which respectively may have 1 to 5 substituents selected from (1) halogen, (2) C1-3 alkylenedioxy, (3) nitro, (4) cyano, (5) C1-6 alkyl that may be halogenated, (6) C2-6 alkenyl that may be halogenated, (7) C2-6 alkynyl that may be halogenated, (8) C3-6 cycloalkyl that may be halogenated, (9) C6-14 aryl, (10) C1-6 alkoxy that may be halogenated, (11) C1-6 alkylthio that may be halogenated or mercapto, (12) hydroxyl, (13) amino, (14) mono-C1-6 alkylamino, (15) mono-C6-14 arylamino, (16) di-C1-6 alkylamino, (17) di-C6-14 arylamino, (18) acyl selected from formyl, carboxyl, carbamoyl, C1-6 alkyl-carbonyl, C3-6 cycloalkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-14 aryl-carbonyl, C7-16 aralkyl-carbonyl, C6-14 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-14 aryl-carbamoyl, thiocarbamoyl, 5- or 6-membered, heterocyclic carbamoyl that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, C1-6 alkylsulfonyl, C6-14 arylsulfonyl, C1-6 alkylsulfinyl and C6-14 arylsulfinyl, (19) acylamino selected from formylamino, C1-6 alkyl-carbonylamino, C6-14 aryl-carbonylamino, C1-6 alkoxy-carbonylamino, C1-6 alkylsulfonylamino and C6-14 arylsulfonylamino, (20) acyloxy selected from C1-6 alkyl-carbonyloxy, C6-14 aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-6 alkyl-carbamoyloxy, C6-14 aryl-carbamoyloxy and nicotinoyloxy, (21) 5- to 7-membered saturated-cyclic amino, which may have 1 to 3 substituents selected from C1-6 alkyl, C6-14 aryl, and a 5- to 10-membered aromatic heterocyclic group that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, (22) a 5- to 10-membered aromatic heterocyclic group that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, (23) sulfo, and (24) a C6-14 aryloxy, or
(iv) R1 and R2 form, together with the adjacent carbon atom, C3-8 cycloalkane or a 3- to 8-membered heterocyclic ring that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, which respectively may have 1 to 5 substituents selected from (1) halogen, (2) C1-3 alkylenedioxy, (3) nitro, (4) cyano, (5) C1-6 alkyl that may be halogenated, (6) C2-6 alkenyl that may be halogenated, (7) C2-6 alkynyl that may be halogenated, (8) C3-6 cycloalkyl that may be halogenated, (9) C6-14 aryl, (10) C1-6 alkoxy that may be halogenated, (11) C1-6 alkylthio that may be halogenated or mercapto, (12) hydroxyl, (13) amino, (14) mono-C1-6 alkylamino, (15) mono-C6-14 arylamino, (16) di-C1-6 alkylamino, (17) di-C6-14 arylamino, (18) acyl selected from formyl, carboxyl, carbamoyl, C1-6 alkyl-carbonyl, C3-6 cycloalkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-14 aryl-carbonyl, C7-16 aralkyl-carbonyl, C6-14 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, thiocarbamoyl, C6-14 aryl-carbamoyl, 5- or 6-membered heterocyclic carbamoyl that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, C1-6 alkylsulfonyl, C6-14 arylsulfonyl, C1-6 alkylsulfinyl and C6-14 arylsulfinyl, (19) acylamino selected from formylamino, C1-6 alkyl-carbonylamino, C6-14 aryl-carbonylamino, C1-6 alkoxy-carbonylamino, C1-6 alkylsulfonylamino and C6-14 arylsulfonylamino, (20) acyloxy selected from C1-6 alkyl-carbonyloxy, C6-14 aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-6 alkyl-carbamoyloxy, C6-14 aryl-carbamoyloxy and nicotinoyloxy, (21) 5- to 7-membered saturated-cyclic amino, which may have 1 to 3 substituents selected from C1-6 alkyl, C6-14 aryl, and a 5- to 10-membered aromatic heterocyclic group that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, (22) a 5- to 10-membered aromatic heterocyclic group that contains, besides the carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, (23) sulfo, and (24) a C6-14 aryloxy;
R3 is C6-14 aryl, which respectively may have 1 to 5 substituents selected from (1) halogen, (2) C1-3 alkylenedioxy, (3) nitro, (4) cyano, (5) C1-6 alkyl that may be halogenated, (6) C2-6 alkenyl that may be halogenated, (7) C2-6 alkynyl that may be halogenated, (8) C3-6 cycloalkyl that may be halogenated, (9) C6-14 aryl, (10) C1-6 alkoxy that may be halogenated, (11) C1-6 alkylthio that may be halogenated or mercapto, (12) hydroxyl, (13) amino, (14) mono-C1-6 alkylamino, (15) mono-C6-14 arylamino, (16) di-C1-6 alkylamino, (17) di-C6-14 arylamino, (18) acyl selected from formyl, carboxyl, carbamoyl, C1-6 alkyl-carbonyl, C3-6 cycloalkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-14 aryl-carbonyl, C7-16 aralkyl-carbonyl, C6-14 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-14 aryl-carbamoyl, thiocarbamoyl, 5- or 6-membered heterocyclic carbamoyl that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, C1-6 alkylsulfonyl, C6-14 arylsulfonyl, C1-6 alkylsulfinyl and C6-14 arylsulfinyl, (19) acylamino selected from formylamino, C1-6 alkyl-carbonylamino, C6-14 aryl-carbonylamino, C1-6 alkoxy-carbonylamino, C1-6 alkylsulfonylamino and C6-14 arylsulfonylamino, (20) acyloxy selected from C1-6 alkyl-carbonyloxy, C6-14 aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-6 alkyl-carbamoyloxy, C6-14 aryl-carbamoyloxy and nicotinoyloxy, (21) 5- to 7-membered saturated-cyclic amino, which may have 1 to 3 substituents selected from C1-6 alkyl, C6-14 aryl, and a 5- to 10-membered aromatic heterocyclic group that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, (22) a 5- to 10-membered aromatic heterocyclic group that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, (23) sulfo, and (24) C6-14 aryloxy;
R4 is (i) a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, or a C3-6 has 1 to 3 groups of a C6-14 aryl group and a 5- to 14-membered, aromatic heterocyclic group that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, which respectively may have 1 to 5 substituents selected from (1) halogen, (2) C1-3 alkylenedioxy, (3) nitro, (4) cyano, (5) C1-6 alkyl that may be halogenated, (6) C2-6, alkenyl that may be halogenated, (7) C2-6 alkynyl that may be halogenated, (8) C3-6 cycloalkyl that may be halogenated (9) C6-14 aryl, (10) C1-6, alkoxy that may be halogenated, (11) C1-6 alkylthio that may be halogenated or mercapto, (12) hydroxyl, (13) amino, (14) mono-C1-6 alkylamino, (15) mono-C6-14 arylamino, (16) di-C1-6 alkylamino, (17) di-C6-14 arylamino, (18) acyl selected from formyl, carboxyl, carbamoyl, C1-6 alkyl-carbonyl, C3-6 cycloalkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-14 aryl-carbonyl, C7-16 alkyl-carbonyl, C6-14 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-14 aryl-carbamoyl, thiocarbamoyl, 5- or 6-membered heterocyclic carbamoyl that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, C6-14 alkylsulfonyl, C6-14 arylsulfonyl, C1-6 alkylsulfinyl and C6-14 arylsulfinyl, (19) acylamino selected from formylamino, C1-6 alkylcarbonylamino, C6-14 aryl-carbonylamino, C1-6 alkoxycarbonylamino, C1-6 alkylsulfonylamino and C6-14 arylsulfonylamino, (20) acyloxy selected from C1-6 alkylcarbonyloxy, C6-14 aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-6 alkyl-carbamoyloxy, C6-14 aryl-carbamoyloxy and nicotinoyloxy, (21) 5- to 7-membered saturated-cyclic amino, which may have 1 to 3 substituents selected from C1 6alkyl, C6-14 aryl, and a 5- to 10-membered aromatic heterocyclic group that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, (22) a 5- to 10-membered aromatic heterocyclic group that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, (23) sulfo, and (24) a C6-14 aryloxy, and further may have 1 to 5 substituents selected from (1) halogen, (2) C3-6 alkylenedioxy, (3) nitro, (4cyano (5) C1-6 alkyl that may be halogenated, (6) C2-6 alkenyl that may be halogenated, (7) C2-6 alkynyl that may be halogenated, (8) C3-6 cycloalkyl that may be halogenated, (9) C6-14 aryl, (10) C1-6 alkoxy that may be halogenated, (11) C1-6 alkylthio that may be halogenated or mercapto, (12) hydroxyl, (13) amino, (14) mono-C1-6 alkylamino, (15) mono-C6-14 arylamino, (16) di-C1 6 alkylamino, (17) di-C6-14 arylamino, (18) acyl selected from formyl, carboxyl, carbamoyl, C1-6 alkyl-carbonyl, C3-6 cycloalkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-14 aryl-carbonyl, C7-16 aralkyl-carbonyl, C6-14 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-14 aryl-carbamoyl, thiocarbamoyl, 5- or 6-membered heterocyclic carbamoyl that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, C1 6alkylsulfonyl, C6-14 arylsulfonyl, C1-6 alkylsulfinyl, and C6-14 arylsulfinyl, (19) acylamino selected from formylamino, C1-6 alkyl-carbonylamino, C6-14aryl-carbonylamino, C1-6 alkoxy-carbonylamino, C1-6 alkylsulfonylamino and C6-14 arylsulfonylamino, (20) acyloxy selected from C1-6 alkylcarbonyloxy, C6-14 aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-6 alkyl-carbamoyloxy, C6-14 aryl-carbamoyloxy and nicotinoyloxy, (21) 5- to 7-membered saturated-cyclic amino which may have 1 to 3 substituents selected from C, 6alkyl, C6-14 aryl and 5- to 10-membered aromatic heterocyclic group that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, (22) a 5- to 10-membered, aromatic heterocyclic group that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, (23) sulfo, and (24) a C6-14 aryloxy, or
(ii) an acyl group that is selected from formyl, carboxyl, carbamoyl, C1-6 alkyl-carbonyl, C3-6 cycloalkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-14 aryl-carbonyl, C7-16 aralkyl-carbonyl, C6-14 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonyl that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-14 aryl-carbamoyl, thiocarbamoyl, 5- or 6-membered heterocyclic carbamoyl that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, C1-6 alkylsulfonyl, C6-14 arylsulfonyl, C1-6 alkylsulfinyl and C6-14 arylsulfinyl,
which have 1 to 3 groups of a C6-14 aryl group and a 5- to 14-membered aromatic heterocyclic group that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, which respectively may have 1 to 5 substituents selected from (1) halogen, (2) C1-3 alkylenedioxy, (3) nitro, (4) cyano, (5) C1-6 alkyl that may be halogenated, (6) C2-6 alkenyl that may be halogenated, (7) C2-6 alkynyl that may be halogenated, (8) C3-6 cycloalkyl that may be halogenated, (9) C6-14 aryl, (10) C1-6 alkoxy that may be halogenated, (11) C1-6 alkylthio that may be halogenated or mercapto, (12) hydroxyl, (13) amino, (14) mono-C1-6 alkylamino, (15) mono-C6-14 arylamino, (16) di-C1-6 alkylamino, (17) di-C6-14 arylamino, (18) acyl selected from formyl, carboxyl, carbamoyl, C1-6 alkyl-carbonyl, C3-6 cycloalkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-14 aryl-carbonyl, C7-16 aralkyl-carbonyl, C6-14 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-membered, heterocyclic carbonyl that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, C6-14 aryl-carbamoyl, thiocarbamoyl, 5- or 6-membered heterocyclic carbamoyl that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, C1-6 alkylsulfonyl, C6-14 arylsulfonyl, C1-6 alkylsulfinyl and C6-14 arylsulfinyl, (19) acylamino selected from formylamino, C1-6 alkyl-carbonylamino, C6-14 aryl-carbonylamino, C1-6 alkoxy-carbonylamino, C1-6 alkylsulfonylamino and C6-14 arylsulfonylamino, (20) acyloxy selected from C1-6 alkyl-carbonyloxy, C6-14 aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy, di-C1-6 alkyl-carbamoyloxy, C6-14 aryl-carbamoyloxy and nicotinoyloxy, (21) 5- to 7-membered, saturated-cyclic amino, which may have 1 to 3 substituents selected from C1-6 alkyl, C6-14 aryl, and a 5- to 10-membered aromatic heterocyclic group that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, (22) a 5- to 10-membered aromatic heterocyclic group that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, (23) sulfo, and (24) C6-14 aryloxy;
20. The compound according to the above 1, wherein R1 and R2 are the same or different and each is hydrogen atom or a C1-6 alkyl group which may be substituted, or R1 and R2 form, together with the adjacent carbon atom, a 3- to 8-membered heterocyclic ring that may be substituted;
21. The compound according to the above 1, wherein each of R1 and R2 is hydrogen atom or a C1-6 alkyl group;
22. The compound according to the above 1, wherein each of R1 and R2 is hydrogen atom or methyl group;
23. The compound according to the above 1, wherein R1 and R2 form, together with the adjacent carbon atom, a ring that is represented by 
xe2x80x83(wherein Z is hydrogen atom or a C1-6 alkyl group);
24. The compound according to the above 1, wherein R3 is phenyl group that may be substituted with halogen or C1-6 alkyl;
25. The compound according to the above 1, wherein R3 is phenyl group that may be substituted with fluorine, methyl or isopropyl;
26. The compound according to the above 1, wherein the substitution position on ring C of a group represented by the formula xe2x80x94NR4 (R5) is 5-position on the benzofuran ring or the dihydrobenzofuran ring;
27. The compound according to the above 1, wherein R4 is (1) a C1-6 alkyl group that is substituted with an aromatic group that may be substituted with halogen, C1-6 alkoxy or C1-3 alkylenedioxy, or (2) an acyl group, which contains an aromatic group that may be substituted with halogen, C1-6 alkoxy or C1-3 alkylenedioxy;
28. The compound according to the above 1, wherein R4 is benzyl group or phenethyl group that may be substituted with fluorine, methoxy or methylenedioxy;
29. The compound according to the above 1, wherein R5 is hydrogen atom, a C1-6 alkyl group or a C1-6 alkyl-carbonyl group;
30. The compound according the above 1, wherein R5 is hydrogen atom or methyl group;
31. The compound according to the above 1, wherein ring C is benzene ring that may be further substituted with 1 to 3 C1-6 alkyl groups;
32. The compound according to the above 1, wherein ring C is benzene ring that is further substituted with 3 methyl groups;
33. The compound according to the above 1, wherein R1 and R2 are the same or different and each is hydrogen atom or a C1-6 alkyl group, or R1 and R2 form, together with the adjacent carbon atom, a piperidine ring that is substituted with C1-6 alkyl;
R3 is phenyl group that may be substituted with halogen or C1-6 alkyl;
R4 is (1) a C1-6 alkyl group that is substituted with C6-14 aryl, thienyl or pyridyl, which may be substituted with halogen, C1-6 alkoxy or C1-3 alkylenedioxy, or (2) a C6-14 aryl-carbonyl group, a C7-16 aralkyl-carbonyl group, a C6-14 arylsulfonyl group, nicotinoyl group or thenoyl group, which may be substituted with halogen, C1-6 alkoxy or C1-3 alkylenedioxy;
R5 is hydrogen atom, a C1-6 alkyl group or a C1-6 alkylcarbonyl group; and
ring C is benzene ring that is further substituted with 1 to 3 C1-6 alkyl groups;
34. The compound according to the above 1, wherein each of R1 and R2 is hydrogen atom or a C1-3 alkyl group;
R3 is a C6-14 aryl group that may be substituted with a halogen atom or C1-6 alkyl;
R4 is a C7-15 aralkyl group that may be substituted with a halogen atom, C1-6 alkoxy or C1-3 alkylenedioxy;
R5 is hydrogen atom or a C1-6 alkyl group;
-- is a single bond; and
ring C is benzene ring that is further substituted with 3 C1-6 alkyl groups;
35. The compound according to above 1, wherein each of R1 and R2 is methyl group;
R3 is phenyl group that may be substituted with fluorine, methyl or isopropyl;
R4 is benzyl group or phenethyl group that may be substituted with fluorine, methoxy or methylenedioxy;
R5 is hydrogen atom or methyl group;
-- is a single bond; and
ring C is benzene ring that is further substituted with 3 methyl groups;
36. [1] N-(4-fluorobenzyl)-2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine, [2] N-benzyl-3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine, [3] 3-(4-isopropylphenyl)-N-(4-methoxybenzyl)-N,2,2,4,6,7-hexamethyl-2,3-dihydro-1-benzofuran-5-amine, [4] 3-(4-isopropylphenyl)-N-[2-(4-methoxyphenyl)ethyl]-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine, [5] N-(4-fluorobenzyl)-3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine, [6] N-(1,3-benzodioxol-5-ylmethyl)-3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine, [7] N-(4-fluorobenzyl)-3-(4-fluorophenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine, [8] N-(4-methoxybenzyl)-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine, [9] N-(4-fluorobenzyl)-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine, [10] 3-(4-isopropylphenyl)-N-(4-methoxybenzyl)-2,4,6,7-tetramethyl-1-benzofuran-5-amine, [11] N-(4-fluorobenzyl)-3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-1-benzofuran-5-amine, [12] N-(4-fluorobenzyl)-3-(4-fluorophenyl)-2,4,6,7-tetramethyl-1-benzofuran-5-amine, [13] N-(4-fluorobenzyl)-3-(4-isopropylphenyl)-1xe2x80x2,4,6,7-tetramethylspiro[benzofuran-2(3H),4xe2x80x2-piperidine]-5-amine, or [14] (+)-N-(4-fluorobenzyl)-3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine hydrochloride;
37. A prodrug of the compound according to the above 1;
38. A process for producing the compound according to the above 1 which comprises reacting a compound represented by the formula: 
xe2x80x83wherein each of the symbol is as defined in the above 2, or a salt thereof with a compound represented by the formula: 
xe2x80x83wherein each of L1 and L2 is a leaving group and ring A is as defined in the above 2, or a salt thereof, or reacting a compound represented by the formula: 
xe2x80x83wherein each symbol is as defined in the above 3, or a salt thereof with a compound represented by the formula: R4-L (wherein L is a leaving group and R4 is as defined in the above 3);
39. A pharmaceutical composition which comprises a compound represented by the formula: 
xe2x80x83wherein R1 and R2 are the same or different and each is hydrogen atom, a hydrocarbon group that may be substituted or a heterocyclic group that may be substituted or R1 and R2 may form, together with the adjacent carbon, a 3- to 8-membered homocyclic or heterocyclic ring that may be subsituted, --- is a single bond or a double bond,
W is
(i) a group represented by the formula: 
xe2x80x83wherein ring A is benzene ring that may be substituted and ring B is a 5- to 7-membered nitrogen-containing heterocyclic ring, which may be substituted with a halogen or a hydrocarbon group that may be substituted, or
(ii) a group represented by the formula: 
xe2x80x83wherein R4 is (1) an aliphatic hydrocarbon group which may be substituted with an aromatic group that may be substituted and, may further be substituted, or (2) an acyl group containing an aromatic group that may be substituted, R5 is hydrogen atom, a C1-6 alkyl group, or an acyl group, when W is Wa, R3 is hydrogen atom, a hydrocarbon group that may be substituted or a heterocyclic group that may be substituted and ring C is benzene ring that may be substituted with, in addition to the group represented by Wa, a substituent selected from halogen, lower alkyl that may be halogenated, lower alkoxy that may be halogenated, and lower alkylthio that may be halogenated,
when W is Wb, R3 is a C6-14 aryl group that may be substituted and ring C is benzene ring that may be further substituted, in addition to the group represented by Wb, provided that, when --- is a double bond, the partial structure: 
xe2x80x83or a salt thereof, or a prodrug thereof;
40. The composition according to the above 39 which is an agent for inhibiting neurodegeneration;
41. The composition according to the above 39 which is an agent for inhibiting cytotoxicity of xcex2-amyloid;
42. The composition according to the above 39 which is an agent for exhibiting a neurotrophic factor-like activity;
43. The composition according to the above 39 which is a drug for preventing or treating neurodegenerative diseases;
44. The composition according to the above 39 which is a drug for preventing or treating Alzheimer""s disease or Parkinson""s disease.
45. A method for treating Alzheimer""s disease or Parkinson""s disease which comprises administrating an effective amount of the compound according to the above 1 or a prodrug thereof to a mammal;
46. Use of the compound according to the above 1 or a prodrug thereof for manufacturing an agent for treating Alzheimer""s disease or Parkinson""s disease;
47. An inhibitor of neurodegeneration which comprises a compound represented by the formula: 
xe2x80x83wherein R1 and R2 are the same or different and each is hydrogen atom, a hydrocarbon group that may be substituted or a heterocyclic group that may be substituted, or R1 and R2 may form, together with the adjacent carbon, a 3- to 8-membered homocylcic or heterocyclic ring that may be substituted,
R3a is hydrogen atom, a hydrocarbon group that may be substituted or a heterocyclic group that may be substituted,
--- indicates a single bond or a double bond,
ring A is benzene ring that may be substituted,
ring Ba is a 5- to 7-membered heterocyclic ring that may be substituted,
ring Ca is benzene ring which may be further substituted, in addition to the group represented by the formula: 
xe2x80x83wherein each symbol is as defined above, or a salt thereof, or a prodrug thereof;
48. The inhibitor according to the above 47 which is an agent for inhibiting cytotoxicity of xcex2-amyloid;
49. The inhibitor according to the above 47 which is an agent for exhibiting a neurotrophic factor-like activity;
50. The inhibitor according to the above 47 which is a drug for preventing or treating neurodegenerative diseases;
51. The inhibitor according to the above 47 which is a drug for preventing of treating Alzheimer""s disease or Parkinson""s disease;
52. A method for treating Alzheimer""s disease or Parkinson""s disease which comprises administrating an effective amount of the compound according the above 47 or a prodrug thereof to a mammal; and
53. Use of the compound according to the above 47 or a prodrug thereof for manufacturing an agent for treating Alzheimer""s disease or Parkinson""s disease.
In the above-mentioned formulas, --- indicates a single bond or a double bond.
In the above-mentioned formulas, R1 and R2 are the same or different and each is hydrogen atom, a hydrocarbon group that may be substituted or a heterocyclic group that may be substituted, or R1 and R2 may form, together with the adjacent carbon, a 3- to 8-membered, homocyclic or heterocyclic ring that may be substituted.
When --- indicates a double bond in the above-mentioned formulas, R2 is not present. In other words, in the above-mentioned formulas,
(i) when --- indicates a single bond, the partial structure: 
(ii) when --- indicates a double bond, the partial structure: 
In the present specification, for convenience, sometimes, the above (i) and (ii) together are represented by the formula: 
Examples of xe2x80x9ca hydrocarbon groupxe2x80x9d of xe2x80x9ca hydrocarbon group that may be substitutedxe2x80x9d indicated by R1 or R2 include a chain or cyclic hydrocarbon group (e.g., alkyl, alkenyl, alkynyl, cycloalkyl, aryl, etc.) or the like. Among them, a chain or cyclic hydrocarbon group having 1 to 16 carbon atoms is preferred.
Examples of xe2x80x9calkylxe2x80x9d include preferably C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), etc.
Examples of xe2x80x9calkenylxe2x80x9d include preferably C2-6 alkenyl (e.g., vinyl, allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl, etc.), etc.
Examples of xe2x80x9calkynylxe2x80x9d include preferably C2-6 alkynyl (e.g., ethynyl, propargyl, butynyl, 1-hexynyl, etc.), etc.
Examples of xe2x80x9ccycloalkylxe2x80x9d include preferably C3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), etc.
Examples of xe2x80x9carylxe2x80x9d include preferably C6-14 aryl (e.g., phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-anthryl, etc.), etc.
Examples of xe2x80x9csubstituent(s)xe2x80x9d of xe2x80x9ca hydrocarbon group that may be substitutedxe2x80x9d indicated by R1 or R2 include (1) halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), (2) C1-3 alkylenedioxy (e.g., methylenedioxy, ethylenedioxy, etc.), (3) nitro, (4) cyano, (5) C1-6 alkyl that may be halogenated, (6) C2-6 alkenyl that may be halogenated, (7) C26 alkynyl that may be halogenated, (8) C3-6 cycloalkyl that may be halogenated, (9) a C6-14 aryl (e.g., phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-anthryl, etc.), (10) C1-6 alkoxy that may be halogenated, (11) C1-6 alkylthio that may be halogenated or mercapto, (12) hydroxyl, (13) amino, (14) mono-C1-6 alkylamino (e.g., methylamino, ethylamino, etc.), (15) mono-C6-14 arylamino (e.g., phenylamino, 1-naphthylamino, 2-naphthylamino, etc.), (16) di-C1-6 alkylamino (e.g., dimethylamino, diethylamino, etc.), (17) di-C6-14 arylamino (e.g., diphenylamino, etc.), (18) acyl, (19) acylamino, (20) acyloxy, (21) 5- to 7-membered saturated-cyclic amino that may be substituted, (22) 5- to 10-membered aromatic heterocyclic group (e.g., 2- or 3-thienyl, 2-, 3-, or 4-pyridyl, 2-, 3-, 4-, 5-, or 8-quinolyl, 1-, 3-, 4-, or 5-isoquinolyl, 1-, 2-, or 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, benzo[b]furanyl, etc.), (23) sulfo, and (24) C6-14 aryloxy (e.g., phenyloxy, 1-naphthyloxy, etc.), etc.
Said xe2x80x9chydrocarbon groupxe2x80x9d may have 1 to 5, preferably 1 to 3 substituents, for example, those as mentioned above, at any substitutable positions. When 2 or more substituents are present, each of them may be the same or different.
Examples of the above-mentioned xe2x80x9cC1-6 alkyl that may be halogenatedxe2x80x9d include C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) that may have 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.) or the like. Specific examples include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl, or the like.
Examples of the above-mentioned xe2x80x9cC2-6 alkenyl that may be halogenatedxe2x80x9d include C2-6 alkenyl (e.g., vinyl, allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl, etc.) that may have 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.), or the like. Specific examples include vinyl, allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl, 3,3,3-trifluoropropenyl, 4,4,4-trifluorobutenyl, or the like.
Examples of the above-mentioned xe2x80x9cC2-6 alkynyl that may be halogenatedxe2x80x9d include C26 alkynyl (e.g., ethynyl, propargyl, butynyl, 1-hexynyl, etc.) that may have 1 to 5, preferably 1 to 3, halogen atoms (for example, fluorine, chlorine, bromine, iodine, and the like) or the like. Specific examples include ethinyl, propargyl, butinyl, 1-hexinyl, 3,3,3-trifluoro-1-propinyl, 4,4,4-trifluoro-1-butinyl, or the like.
Examples of the above-mentioned xe2x80x9cC3-6 cycloalkyl that may be halogenatedxe2x80x9d include C3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) that may have 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.), or the like. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4-dichlorocyclohexyl, 2,2,3,3,-tetraflourocyclopentyl, 4-chlorocyclohexyl, or the like.
Examples of the above-mentioned xe2x80x9cC1-6 alkoxy that may be halogenatedxe2x80x9d include C1-6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.) that may have 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.) or the like. Specific examples include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, or the like.
Examples of the above-mentioned xe2x80x9cC1-6 alkylthio that may be halogenatedxe2x80x9d include C1-6 alkylthio (e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, etc.) that may have 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.) or the like. Specific examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio, or the like.
Examples of the above-mentioned xe2x80x9cacylxe2x80x9d include formyl, carboxyl, carbamoyl, C1-6 alkylcarbonyl (e.g., acetyl, propionyl, etc.), C3-6 cycloalkylcarbonyl (e.g., cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), C1-6 alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.), C6-14 arylcarbonyl (e.g., benzoyl, 1-naphthoyl, 2-naphthoyl, etc.), C7-16 aralkylcarbonyl (e.g., phenylacetyl, phenylpropionyl, etc.), C6-14 aryloxycarbonyl (e.g., phenoxycarbonyl, etc.), C7-16 aralkyloxycarbonyl (e.g., benzyloxycarbonyl, phenethyloxycarbonyl, etc.), 5- or 6-membered heterocyclic carbonyl (e.g., nicotinoyl, isonicotinoyl, 2-thenoyl, 3-thenoyl, 2-furoyl, 3-furoyl, morpholinocarbonyl, thiomorpholinocarbonyl, piperidinocarbonyl, 1-pyrrolidinylcarbonyl, etc.), mono-C1-6 alkylcarbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl, etc.), di-C1-6 alkylcarbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.), C6-14 arylcarbamoyl (e.g., phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl, etc.), thiocarbamoyl, 5- or 6-membered, heterocyclic carbamoyl (e.g., 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl, etc.), C1-6 alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, etc.), C6-14 arylsulfonyl (e.g., phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, etc.), C1-6 alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl, etc.), and C6-14 arylsulfinyl (e.g., phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl, etc.), or the like.
Examples of the above-mentioned xe2x80x9cacylaminoxe2x80x9d include formylamino, C1-6 alkylcarbonylamino (e.g., acetylamino, etc.), C6-14 arylcarbonylamino (e.g., phenylcarbonylamino, naphthylcarbonylamino, etc.), C1-6 alkoxycarbonylamino (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, etc.), C1-6 alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino, etc.), and C6-14 arylsulfonylamino (e.g., phenylsulfonylamino, 2-naphthylsulfonylamino, 1-naphthylsulfonylamino, etc.), or the like.
Examples of the above-mentioned xe2x80x9cacyloxyxe2x80x9d include C1-6 alkylcarbonyloxy (e.g., acetoxy, propionyloxy, etc.), C6-14 arylcarbonyloxy (e.g., benzoyloxy, naphthylcarbonyloxy, etc.), C1-6 alkoxycarbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, etc.), mono-C1-6 alkylcarbamoyloxy (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, etc.), di-C1-6 alkylcarbamoyloxy (e.g., dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.), C6-14 arylcarbamoyloxy (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy, etc.), nicotinoyloxy, or the like.
Examples of xe2x80x9c5- to 7-membered saturated cyclic aminoxe2x80x9d of the above-mentioned xe2x80x9c5- to 7-membered saturated cyclic amino that may be substitutedxe2x80x9d include morpholino, thiomorpholino, piperazin-1-yl, piperidino, pyrrolidin-1-yl, or the like. Examples of the xe2x80x9csubstituent(s)xe2x80x9d of said xe2x80x9c5- to 7-membered saturated cyclic amino that may be substitutedxe2x80x9d include 1 to 3 substituents selected from C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), C6-14 aryl (e.g., phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-anthryl, etc.), a 5- to 10-membered aromatic, heterocyclic group (e.g., 2- or 3-thienyl, 2-, 3-, or 4-pyridyl, 2-, 3-, 4-, 5-, or 8-quinolyl, 1-, 3-, 4-, or 5-isoquinolyl, 1-, 2-, or 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, benzo[b]furanyl, etc.), and the like.
Examples of xe2x80x9ca heterocyclic groupxe2x80x9d of xe2x80x9ca heterocyclic group that may be substitutedxe2x80x9d indicated by R1 or R2 include a 5- to 14-membered, heterocyclic group that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom (an aromatic heterocyclic group, or a saturated or unsaturated non-aromatic heterocyclic group) or the like.
Examples of said xe2x80x9caromatic heterocyclic groupxe2x80x9d include a 5- to 14-membered, preferably 5- to 10-membered aromatic heterocyclic group that contains, in addition to carbon atom, 1 or more (for example, 1 to 4) hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, or the like. Specific examples include a monovalent group formed by removing an optional hydrogen atom from an aromatic heterocyclic ring such as thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, isoindolizine, xantholene, phenoxatine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H-indazole, purine, 4H-quinolidine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, xcex2-carboline, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isoxazole, furazane, phenoxazine, etc., or a ring formed by condensing the above ring (preferably a monocyclic ring) with 1 to plural (preferably, 1 or 2) aromatic rings (e.g., benzene ring, etc.), and the like.
Examples of xe2x80x9can aromatic heterocyclic groupxe2x80x9d include preferably a 5- to 10-membered aromatic heterocyclic group that may be condensed with a benzene ring. Specific examples include 2-, 3-, or 4-pyridyl, 2-, 3-, 4-, 5-, or 8-quinolyl, 1-, 3-, 4-, or 5-isoquinolyl, 1-, 2-, or 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, benzo[b]furanyl, 2- or 3-thienyl, or the like. More preferred examples include 2- or 3-thienyl, 2-, 3-, or 4-pyridyl, 2- or 3-quinolyl, 1-isoquinolyl, 1- or 2-indolyl, 2-benzothiazolyl, and the like.
Examples of xe2x80x9ca non-aromatic heterocyclic groupxe2x80x9d include a 3- to 8-membered (preferably, 5- or 6-membered), saturated or unsaturated (preferably, saturated), non-aromatic heterocyclic group (an aliphatic heterocyclic group) such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, or the like.
As for xe2x80x9csubstituent(s)xe2x80x9d of xe2x80x9ca heterocyclic group that may be substitutedxe2x80x9d indicated by R1 or R2, the same number and the xe2x80x9csubstituent(s)xe2x80x9d as those of xe2x80x9ca hydrocarbon group that may be substitutedxe2x80x9d indicated by R1 or R2 can be employed.
Examples of xe2x80x9ca 3- to 8-membered homocyclic ringxe2x80x9d of xe2x80x9ca 3- to 8-membered homocyclic ring that may be substitutedxe2x80x9d formed by R1 and R2 include C3-6 cycloalkane such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, or the like.
Examples of xe2x80x9ca 3- to 8-membered heterocyclic ringxe2x80x9d of xe2x80x9ca 3- to 8-membered heterocyclic ring that may be substitutedxe2x80x9d formed by R1 and R2 include a 3- to 8-membered heterocyclic group that contains, in addition to carbon atom, 1 to 4 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, such as aziridine, azetidine, morpholine, thiomorpholine, piperazine, piperidine, pyrrolidine, hexamethyleneimine, heptamethyleneimine, hexahydropyrimidine, or the like.
As for xe2x80x9csubstituent(s)xe2x80x9d of xe2x80x9ca 3- to 8-membered homocyclic or heterocyclic ring that may be substitutedxe2x80x9d formed by R1 and R2, the same number and the same xe2x80x9csubstituentsxe2x80x9d as those of xe2x80x9ca hydrocarbon group that may be substitutedxe2x80x9d indicated by R1 or R2 can be employed.
In the above-mentioned formulas, W indicates
(i) a group represented by the formula: 
xe2x80x83wherein ring A is benzene ring that may be substituted and ring B is a 5- to 7-membered nitrogen-containing heterocyclic ring, which may be substituted with a halogen or a hydrocarbon group that may be substituted, or
(ii) a group represented by the formula: 
xe2x80x83wherein R4 is (1) an aliphatic hydrocarbon group which may be substituted with an aromatic group that may be substituted and, may further be substituted, or (2) an acyl group containing an aromatic group that may be substituted, R5 is hydrogen atom, a C1-6 alkyl group, or an acyl group.
When W is Wa, in the above-mentioned formulas, R3 is hydrogen atom, a hydrocarbon group that may be substituted or a heterocyclic group that may be substituted (hereinafter, sometimes, referred to as R3a).
As for xe2x80x9ca hydrocarbon group that may be substitutedxe2x80x9d and xe2x80x9ca heterocyclic group that may be substitutedxe2x80x9d indicated by R3a, the same groups as the above-mentioned xe2x80x9chydrocarbon group that may be substitutedxe2x80x9d and xe2x80x9ca heterocyclic group that may be substitutedxe2x80x9d indicated by R1 or R2 can be employed.
In the above-mentioned formulas, ring A indicates benzene ring that may be substituted.
The xe2x80x9csubstituent(s)xe2x80x9d of the xe2x80x9cbenzene ring that may be substitutedxe2x80x9d indicated by ring A may have 1 to 4 (preferably 1 or 2) groups, which are the same as the above-mentioned xe2x80x9csubstituent(s)xe2x80x9d of xe2x80x9ca hydrocarbon group that may be substitutedxe2x80x9d indicated by R1 or R2, at substitutable positions. When the number of the substituents is 2 or more, the substituents may be the same or different.
In the above-mentioned formulas, ring B indicates a 5- to 7-membered nitrogen-containing heterocyclic ring which may be substituted with a halogen or a hydrocarbon group that may be substituted.
Examples of xe2x80x9ca 5- to 7-membered, nitrogen-containing, heterocyclic ringxe2x80x9d indicated by ring B include a 5- to 7-membered nitrogen-containing heterocyclic ring or the like such as pyrrole (e.g., 1H-pyrrole, etc.), dihydropyrrole (e.g., 2,5-dihydro-1H-pyrrole, etc.), dihydropyridine (e.g., 1,2-dihydropyridine, etc.), tetrahydropyridine (e.g., 1,2,3,4-tetrahyropyridine, etc.), azepine (e.g., 1H-azepine, etc.), dihydroazepine (e.g., 2,3-dihydro-1H-azepine, 2,5-dihydro-1H-azepine, 2,7-dihydro-1H-azepine, etc.), tetrahydroazepine (for example, 2,3,6,7-tetrahydro-1H-azepine, 2,3,4,7-tetrahydro-1H-azepine, etc.), or the like.
xe2x80x9cA halogenxe2x80x9d as xe2x80x9cthe substituentxe2x80x9d, which ring B may have, is exemplified by fluorine, chlorine, bromine, iodine, or the like.
As for xe2x80x9ca hydrocarbon group that may be substitutedxe2x80x9d, which ring B may have, the same group as the above-mentioned xe2x80x9chydrocarbon group that may be substitutedxe2x80x9d indicated by R1 or R2 can be employed.
Ring B may have 1 to 3 substituents as indicated above at substitutable positions. When the number of the substituents is 2 or more, the substituents may be the same or different.
Specific examples of a group represented by the formula: 
wherein each symbol is as defined above, include groups represented by formulas: 
wherein R6 and R7 are the same or different and each is hydrogen atom, halogen, or a hydrocarbon group that be substituted, and ring A is as defined above, and the like. Preferred are groups represented by 
wherein each symbol is as defined above, and the like, and, more preferred are groups represented by 
wherein each symbol is as defined above, and the like, among which, particularly preferably groups represented by 
wherein each symbol is as defined above, and the like.
As for xe2x80x9chalogenxe2x80x9d or xe2x80x9ca hydrocarbon group that may be substitutedxe2x80x9d indicated by R6 and R7, the same groups as xe2x80x9chalogenxe2x80x9d or xe2x80x9ca hydrocarbon group that may be substitutedxe2x80x9d as the xe2x80x9csubstituentsxe2x80x9d of the above-mentioned ring B can be employed.
In the above-mentioned formulas, ring Ba indicates a 5- to 7-membered nitrogen-containing heterocyclic ring that may be substituted.
As for xe2x80x9ca 5- to 7-membered nitrogen-containing heterocyclic ringxe2x80x9d indicated by ring Ba, the same ring as the xe2x80x9c5- to 7-membered nitrogen-containing heterocyclic ringxe2x80x9d indicated in the above-mentioned ring B can be employed.
As for xe2x80x9csubstituent(s)xe2x80x9d of xe2x80x9ca 5- to 7-membered nitrogen-containing, heterocyclic ring that may be substitutedxe2x80x9d indicated by ring Ba, in addition to xe2x80x9ca halogenxe2x80x9d and xe2x80x9ca hydrocarbon group that may be substitutedxe2x80x9d, which ring B may have, the same number and the same xe2x80x9csubstituent(s)xe2x80x9d as those of the above-mentioned xe2x80x9chydrocarbon group that may be substitutedxe2x80x9d indicated by R1 or R2 can be employed. Also, oxo group and the like are employed as the substituent(s) of ring Ba.
When W is Wa, in the above-mentioned formula, ring C is benzene ring that may further be substituted with, in addition to the group represented by the formula: 
wherein each symbol is as defined above, a substituent selected from halogen, lower alkyl that may be halogenated, lower alkoxy that may be halogenated, and lower alkylthio that may be halogenated (hereinafter, sometimes, referred to as ring C1).
Ring C1 may have 1 to 3 (preferably, 1) substituents as indicated by formula 
at substitutable positions. When the number of the substituents is 2 or more, the substituents may be the same or different.
xe2x80x9cA halogenxe2x80x9d as xe2x80x9cthe substituentxe2x80x9d, which ring C1 may further have, is exemplified by fluorine, chlorine, bromine, iodine, or the like. xe2x80x9cLower alkyl that may be halogenatedxe2x80x9d is exemplified by C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) that may have 1 to 5, preferably 1 to 3, halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.), etc. Specific examples include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl, or the like. xe2x80x9cLower alkoxy that may be halogenatedxe2x80x9d is exemplified by C1-6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, or the like) that may have 1 to 5, preferably 1 to 3, halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.), or the like. Specific examples include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, or the like. xe2x80x9cLower alkylthio that may be halogenatedxe2x80x9d is exemplified by C1-6 alkylthio (e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, etc.) that may have 1 to 5, preferably 1 to 3, halogen atoms (e.g., fluorine, chlorine, bromine, iodine, etc.), or the like. Specific examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio, or the like.
Ring C1 may have 1 to 3 (preferably, 3) substituents as indicated above at substitutable positions. When the number of the substituents is 2 or more, the substituents may be the same or different.
In the above-mentioned formula, ring Ca is benzene ring that may further be substituted, in addition to a group represented by the formula: 
wherein each symbol is as defined above.
Ring Ca may have 1 to 3 (preferably, 1) groups as indicated by the formula: 
at substitutable positions. When the number of the substituents is 2 or more, the substituents may be the same or different.
As for xe2x80x9csubstituent(s)xe2x80x9d, which ring Ca may further have, the same xe2x80x9csubstituentsxe2x80x9d as those of the above-mentioned xe2x80x9chydrocarbon group that may be substitutedxe2x80x9d indicated by R1 or R2 are employed. Also, xe2x80x9cC1-6 alkylxe2x80x9d as for xe2x80x9csubstituent(s)xe2x80x9d of ring Ca may be substituted with xe2x80x9ca 4- to 8-membered lactone that may be substituted with hydroxyl or the like (e.g., 3-hydroxy-xcex4-valerolactone, etc.)xe2x80x9d. Ring Ca may have 1 to 3 (preferably, 3) substituents as indicated above at substitutable positions. when the number of the substituents is 2 or more, the substituents may be the same or different.
When W indicates Wb, in the above-mentioned formulas, R3 indicates a C6-14 aryl group that may be substituted (hereinafter, sometimes, referred to as R3b).
xe2x80x9cC6-14 arylxe2x80x9d of xe2x80x9ca C6-14 aryl group that may be substitutedxe2x80x9d indicated by R3b is exemplified by C6-14 aryl such as phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, anthryl, or the like.
As for xe2x80x9csubstituent(s)xe2x80x9d of said xe2x80x9cC6-14 aryl group that may be substitutedxe2x80x9d, the same number and the same xe2x80x9csubstituent(s)xe2x80x9d as those of the above-mentioned xe2x80x9chydrocarbon group that may be substitutedxe2x80x9d indicated by R1 or R2 can be employed.
In the above-mentioned formulas, R4 indicates (1) an aliphatic hydrocarbon group, which may be substituted with an aromatic group that may be substituted and, may further be substituted, or (2) an acyl group containing an aromatic group that may be substituted.
Examples of xe2x80x9can aromatic groupxe2x80x9d of xe2x80x9can aromatic group that may be substitutedxe2x80x9d as the substituent(s) of xe2x80x9can aliphatic hydrocarbon group, which may be substituted with an aromatic group that may be substituted and, may further be substitutedxe2x80x9d indicate by R4 include an aromatic hydrocarbon group, an aromatic heterocyclic group, or the like.
Said xe2x80x9caromatic hydrocarbon groupxe2x80x9d as defined above is exemplified by a monocyclic or condensed polycyclic (bi- or tricyclic), aromatic, hydrocarbon group having 6 to 14 carbon atoms. Specific examples include C6-14 aryl such as phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, anthryl, or the like or the like, preferably a C6-10 such as phenyl, 1-naphthyl, 2-naphthyl, or the like.
Said xe2x80x9caromatic heterocyclic groupxe2x80x9d is exemplified by a 5- to 14-membered, preferably 5- to 10-membered, aromatic heterocyclic group that contains, in addition to carbon atom, 1 or more (for example, 1 to 4) hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, or the like. Specific examples include a monovalent group, which may be formed by removing an optional hydrogen atom from an aromatic heterocyclic ring such as thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, isoindolizine, xantholene, phenoxatine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H-indazole, purine, 4H-quinolidine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, xcex2-carboline, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isoxazole, furazane, phenoxazine, or the like or a ring, which is formed by condensing these rings (preferably a monocyclic ring) with 1 to plural (preferably, 1 or 2) aromatic rings (for example, benzene ring, etc.), and so on.
xe2x80x9cAn aromatic heterocyclic groupxe2x80x9d is exemplified preferably by a 5- to 10-membered aromatic heterocyclic group that may be condensed with benzene ring. Specific examples include 2-, 3-, or 4-pyridyl, 2-, 3-, 4-, 5-, or 8-quinolyl, 1-, 3-, 4-, or 5-isoquinolyl, 1-, 2-, or 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, benzo[b]furanyl, 2- or 3-thienyl, or the like. More preferable examples include 2- or 3-thienyl, 2-, 3-, or 4-pyridyl, 2- or 3-quinolyl, 1-isoquinolyl, 1- or 2-indolyl, 2-benzothiazolyl, and the like.
As for xe2x80x9csubstituent(s)xe2x80x9d of said xe2x80x9caromatic group that may be substitutedxe2x80x9d, the same number and the same xe2x80x9csubstituent(s)xe2x80x9d as those of the above-mentioned xe2x80x9chydrocarbon group that may be substitutedxe2x80x9d indicated by R1 or R2 can be employed.
xe2x80x9cAn aliphatic hydrocarbon groupxe2x80x9d of xe2x80x9can aliphatic hydrocarbon group, which may be substituted with an aromatic group that may be substituted and, may further be substitutedxe2x80x9d indicate by R4 is exemplified by alkyl, alkenyl, alkynyl, cycloalkyl, or the like. Among them, C1-6 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, and the like are preferred.
Preferred examples of xe2x80x9calkylxe2x80x9d include C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) or the like.
Preferred examples of xe2x80x9calkenylxe2x80x9d include C2-6 alkenyl (e.g., vinyl, allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl, etc.) or the like.
Preferred examples of xe2x80x9calkynylxe2x80x9d include C2-6 alkynyl (for example, ethynyl, propargyl, butynyl, 1-hexynyl, etc.) or the like.
Preferred examples of xe2x80x9ccycloalkylxe2x80x9d include C3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) or the like.
Among them, C1-6 alkyl is preferred.
Said xe2x80x9caliphatic hydrocarbon groupxe2x80x9d may have 1 to 3 xe2x80x9caromatic groups that may be substitutedxe2x80x9d at substitutable positions. When the number of the substituents is 2 or more, the substituents may be the same or different.
As for xe2x80x9csubstituent(s)xe2x80x9d, which said xe2x80x9caliphatic hydrocarbon groupxe2x80x9d may further have, the same number and the same xe2x80x9csubstituent(s)xe2x80x9d as those of the above-mentioned xe2x80x9chydrocarbon group that may have substituentsxe2x80x9d indicated by R1 or R2 can be employed.
As for xe2x80x9can acyl groupxe2x80x9d of xe2x80x9can acyl group containing an aromatic group that may be substitutedxe2x80x9d indicated by R4, the same group as xe2x80x9can acyl groupxe2x80x9d as xe2x80x9csubstituentsxe2x80x9d of the above-mentioned xe2x80x9chydrocarbon group that may have substituentsxe2x80x9d indicated by R1 or R2 can be employed.
As for xe2x80x9can aromatic group that may be substitutedxe2x80x9d of xe2x80x9can acyl group containing an aromatic group that may be substitutedxe2x80x9d indicated by R4, the same group as xe2x80x9can aromatic group that may be substitutedxe2x80x9d of the above-mentioned xe2x80x9can aliphatic hydrocarbon group, which may be substituted with an aromatic group that may be substituted and, may further be substitutedxe2x80x9d indicate by R4 can be employed.
Preferred specific examples of xe2x80x9can acyl group containing an aromatic group that may be substitutedxe2x80x9d indicated by R4 include a C6-14 arylcarbonyl (e.g., benzoyl, 1-naphthoyl, 2-naphthoyl, etc.), C7-16 aralkylcarbonyl (e.g., phenylacetyl, phenylpropionyl, etc.), C6-14 aryloxycarbonyl (e.g., phenoxycarbonyl, etc.), C7-16 aralkyloxycarbonyl (e.g., benzyloxycarbonyl, phenethyloxycarbonyl, etc.), 5- or 6-membered heterocyclic carbonyl (e.g., nicotinoyl, isonicotinoyl, 2-thenoyl, 3-thenoyl, 2-furoyl, 3-furoyl, morpholinocarbonyl, thiomorpholinocarbonyl, piperidinocarbonyl, 1-pyrrolidinylcarbonyl, etc.), C6-14 arylcarbamoyl (e.g., phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl, etc.), 5- or 6-membered heterocyclic carbamoyl (e.g., 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl, etc.), C6-14 arylsulfonyl (e.g., phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, etc.), C6-14 arylsulfinyl (e.g., phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl, etc.), and the like.
In the above-mentioned formulas, R5 is hydrogen atom, a C1-6 alkyl group, or an acyl group
Examples of xe2x80x9cC1-6 alkylxe2x80x9d indicated by R5 include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, or the like.
As for xe2x80x9can acyl groupxe2x80x9d indicated by R5, the same group as xe2x80x9can acyl groupxe2x80x9d as xe2x80x9csubstituentsxe2x80x9d of the above-mentioned xe2x80x9chydrocarbon group that may be substitutedxe2x80x9d indicated by R1 or R2 can be employed.
When W is Wb, in the above-mentioned formulas, ring C is benzene ring that may be further substituted, in addition to the group represented by formula xe2x80x94NR4(R5) (hereinafter, sometimes referred to as ring C2).
Ring C2 may have 1 to 3 groups represented by formula xe2x80x94NR4(R5) at substitutable positions. When the number of the substituents is 2 or more, the substituents may be the same or different.
Examples of xe2x80x9csubstituent(s)xe2x80x9d, which ring C2 may further have, in addition to the group represented by formula xe2x80x94NR4(R5), include a halogen atom (for example, fluorine, chlorine, bromine, iodine, or the like), C1-3 alkylenedioxy(for example, methylenedioxy, ethylenedioxy, or the like), nitro, cyano, C1-6 alkyl that may be halogenated, C2-6 alkenyl that may be halogenated, C2-6 alkynyl that may be halogenated, C3-6 cycloalkyl that may be halogenated, C6-14 aryl (e.g., phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, 2-anthryl, etc.), C1-6 alkoxy that may be halogenated, hydroxyl, amino, mono-C1-6 alkylamino(e.g., methylamino, ethylamino, etc.), mono-C6-14 arylamino (e.g., phenylamino, 1-naphthylamino, 2-naphthylamino, etc.), di-C1-6 alkylamino (e.g., dimethylamino, diethylamino, etc.), di-C6-14 arylamino (e.g., diphenylamino, etc.), acyl, acylamino, 5- to 7-membered saturated-cyclic amino that may be substituted, a 5- to 10-membered aromatic heterocyclic group (e.g., 2- or 3-thienyl, 2-, 3-, or 4-pyridyl, 2-, 3-, 4-, 5-, or 8-quinolyl, 1-, 3-, 4-, or 5-isoquinolyl, 1-, 2-, or 3-indolyl, 2-benzothiazolyl, 2-benzo[b]thienyl, benzo[b]furanyl, etc.), sulfo, and the like.
Said xe2x80x9cC1-6 alkyl that may be halogenatedxe2x80x9d, xe2x80x9cC2-6 alkenyl that may be halogenatedxe2x80x9d, xe2x80x9cC2-6 alkynyl that may be halogenatedxe2x80x9d, xe2x80x9cC3-6 cycloalkyl that may be halogenatedxe2x80x9d, xe2x80x9cC1-6 alkoxy that may be halogenatedxe2x80x9d, xe2x80x9cacylxe2x80x9d, xe2x80x9cacylaminoxe2x80x9d, and xe2x80x9c5- to 7-membered saturated-cyclic amino that may be substitutedxe2x80x9d include, for example, the same groups as those described in detail as xe2x80x9csubstituentsxe2x80x9d of the above-mentioned xe2x80x9chydrocarbon group that may be substitutedxe2x80x9d indicated by R1 or R2.
Ring C2 may have 1 to 3 of said groups at substitutable positions. When the number of the substituents is 2 or more, the substituents may be the same or different.
In this way, there are included in compounds (I) of the present invention compounds (Ia) represented by the formula: 
wherein each symbol is as defined above and compounds (Ib) represented by the formula: 
wherein each symbol is as defined above.
In the above-mentioned compounds (Ia), R1 and R2 are the same or different and, for example, each is preferably hydrogen atom or a C1-6 alkyl group that may be substituted (particularly, a C1-3 alkyl group such as methyl, etc.), or R1 and R2 form, together with the adjacent carbon atom, a 3- to 8-membered heterocyclic ring that may be substituted, or the like, among which each of R1 and R2 is a C1-6 alkyl group, or the like is more preferred. Also, when ---indicates a double bond, R2 is not present and, as for R1, a C1-6 alkyl group that may be substituted is preferred and, particularly, a C1-3 alkyl group such as methyl or the like is preferred.
As for R3a, for example, a C6-14 aryl group that may be substituted or the like is preferred.
As for ring A, for example, benzene ring, which may be substituted with a substituent selected from halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylenedioxy, etc. is preferred.
As for ring B, for example, a 5- to 7-membered nitrogen-containing heterocyclic ring, which may be substituted with a C1-6 alkyl, or the like is preferred.
As for ring C1, benzene ring, which may be further substituted with 1 to 3 C1-6 alkyl groups or C1-6 alkoxy groups, or the like is preferred.
As for a group represented by the formula: 
wherein each symbol is as defined above, a group represented by the formula: 
wherein each symbol is as defined above, or the like is preferred. Particularly, as for R6 and R7, hydrogen atom is preferred and, as for ring A, benzene ring, which may be further substituted with 1 to 2 substituents selected from halogen, C1-6 alkoxy group and C1-6 alkylenedioxy, is preferred.
The substitution position on ring C1 in a group represented by the formula: 
wherein each symbol is as defined in claim 1, is preferably 5-position on the benzofuran ring or the dihydrobenzofuran ring, or the like.
Also, as for compound (Iaxe2x80x2), compounds (Ia) or the like is preferred. As for ring Ba, for example, a 5- to 7-membered nitrogen-containing heterocyclic ring, which may be substituted with C1-6 alkyl, or the like is preferred and, as for ring Ca, benzene ring, which may be further substituted with 1 to 3 C1-6 alkyl groups or C1-6 alkoxy groups, or the like is preferred.
Particularly, as for compound (Ia), that wherein each of R1 and R2is a C1-6 alkyl group (particularly, a C1-3 alkyl group such as methyl, etc.), R3a is phenyl group that may have C1-6 alkyl (particularly, C1-3 alkyl such as methyl, ethyl, isopropyl, etc.) or a halogen atom (particularly, fluorine), ring A is benzene ring, which may have substituent(s) selected from halogen, C1-6 alkyl (particularly, C1-3 alkyl such as methyl, etc.), C1-6 alkoxy (particularly, C1-3 alkoxy such as methoxy, etc.), and C1-6 alkylenedioxy (particularly, C1-3 alkylenedioxy such as methylenedioxy, etc.), ring B is a 5- to 7-membered nitrogen-containing heterocyclic ring, which may be substituted with C1-6 alkyl, and ring C1 is benzene ring, which may be further substituted with 1 to 3 C1-6 alkyl groups (particularly, C1-3 alkyl groups such as methyl, etc.) or C1-6 alkoxy groups (particularly, C1-3 alkoxy groups such as methoxy, etc.), is preferred and, particularly, that wherein a group represented by the formula: 
wherein each symbol is as defined above is a group represented by the formula: 
wherein ring A1 is benzene ring, which may be substituted with 1 to 2 substituents selected from halogen, C1-6 alkoxy, and C1-6 alkylenedioxy, is preferred.
Also, when --- indicates a double bond, R2 is not present and, as for R1, a C1-6 alkyl group or the like that may be substituted is preferred and, particularly, a C1-3 alkyl group such as methyl or the like is preferred. As for the other symbols, the same symbols as those described above are preferable, in particular, the compound wherein R3a, is phenyl group that may have C1-6 alkyl (particularly, C1-3 alkyl such as methyl, ethyl, isopropyl, etc.), ring A is benzene ring, ring B is a 5- to 7-membered nitrogen-containing heterocyclic ring, and ring C1 is benzene ring, which may be further substituted with 1 to 3 C1-6 alkyl groups (particularly, C1-3 alkyl groups such as methyl, etc.), are preferred and, particularly, the compound wherein a group represented by the formula: 
wherein each symbol is as defined above, is a group represented by the formula: 
is preferred.
As for specific examples of compound (Ia), the compounds or salts thereof, which are produced in Example 1a to Example 22a described hereinafter, and the like are preferable, among which,
[1] 2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindoline (Example 4a) or a salt thereof,
[2] 5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindoline (Example 6a) or a salt thereof,
[3] 5,6-dimethoxy-2-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]isoindoline (Example 11a) or a salt thereof,
[4] 6-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]-6,7-dihydro-5H-[1,3]dioxolo[4,5-f]isoindole (Example 12a) or a salt thereof,
[5] 6-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]-6H-[1,3]dioxolo[4,5-f]isoindole (Example 14a) or a salt thereof,
[6] 6-[2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-yl]-6,7-dihydro-5H-[1,3]dioxolo[4,5-f]isoindole (Example 16a) or a salt thereof,
[7] (+)-5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindoline (Example 17a),
[8] (+)-5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindoline hydrochloride (Example 19a), or other salts thereof, and the like are preferable and, particularly,
[1] 5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindoline (Example 6a),
[2] 6-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]-6,7-dihydro-5H-[1,3]dioxolo[4,5-f]isoindole (Example 12a),
[3] (+)-5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindoline (Example 17a),
[4] (+)-5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindoline hydrochloride (Example 19a), and the like are preferable.
In the above-mentioned compounds (Ib), R1 and R2 are the same or different and each is preferably exemplified by hydrogen atom or a C1-6 alkyl group that may be substituted (particularly, a C1-3 alkyl group such as methyl, etc.) or, R1 and R2 form, together with the adjacent carbon atom, a 3- to 8-membered heterocyclic ring that may be substituted (particularly, a 5- or 6-membered nitrogen-containing heterocyclic ring such as piperidine, etc.), or the like, and is more preferably exemplified by hydrogen atom or a C1-6 alkyl group that may be substituted (particularly, a C1-3 alkyl group such as methyl, etc.) or, R1 and R2 form, together with the adjacent carbon atom, a piperidine ring that is substituted with C1-6 alkyl, or the like. Among them, more preferably, each of R1 and R2 is a C1-6 alkyl group, in particular, each is methyl group.
As for R3b, for example, phenyl group that may be substituted with halogen (particularly, fluorine) or C1-6 alkyl (particularly, C1-3 alkyl such as methyl, ethyl, isopropyl, etc.) or the like is preferred and phenyl group that may be substituted with fluorine, methyl, isopropyl or the like is more preferred.
As for R4, (1) a C1-6 alkyl group that may be substituted with an aromatic group (particularly, a C6-14 aryl group such as phenyl or a 5- or 6-membered heterocyclic carbonyl that contains, in addition to carbon atom, 1 to 3 hetero atoms selected from nitrogen atom, sulfur atom and oxygen atom, such as, thienyl, pyridyl, etc.), which may be substituted with halogen, C1-6 alkoxy, or C1-3 alkylenedioxy, or (2) an acyl group that contains an aromatic group (particularly, a C6-14 aryl group such as phenyl), which may be substituted with halogen, C1-6 alkoxy, or C1-3 alkylenedioxy, or the like is preferred. (1) A C1-6 alkyl group (particularly, a C1-3 alkyl group such as methyl) that may be substituted with C6-14 aryl (particularly, phenyl), thienyl, or pyridyl, which may be substituted with halogen (particularly, fluorine or chlorine), C1-6 alkoxy (particularly, a C1-3 alkoxy group such as methoxy), or a C1-3 alkylenedioxy (particularly, methylenedioxy), or (2) a C6-14 arylcarbonyl group (particularly, phenylcarbonyl group), a C7-16 aralkylcarbonyl group (particularly, benzylcarbonyl group), a C6-14 arylsulfonyl group (particularly, phenylsulfonyl group), nicotinoyl group, or thenoyl group, which may be substituted with halogen (particularly, fluorine or chlorine), C1-6 alkoxy (particularly, a C1-3 alkoxy group such as methoxy), or C1-3 alkylenedioxy (particularly, methylenedioxy), or the like is more preferred. Among them, benzyl group or phenethyl group, which may be substituted with fluorine, methoxy or methylenedioxy, or the like is particularly preferred.
As for R5, for example, hydrogen atom, a C1-6 alkyl group (particularly, a C1-3 alkyl group such as methyl), or a C1-6 alkylcarbonyl group (particularly, a C1-3 alkylcarbonyl group such as acetyl), or the like is preferred, and hydrogen atom or methyl group, etc. is more preferred.
As for ring C2, benzene ring that may be further substituted with 1 to 3 C1-6 alkyl groups (particularly, a C1-3 alkyl group such as methyl) or the like is preferred and benzene ring, which may be further substituted with 3 methyl groups, or the like is particularly preferred.
Particularly, as for compounds (Ib), the compound wherein R1 and R2 is the same or different and each is hydrogen atom or a C1-6 alkyl group (particularly, a C1-3 alkyl group such as methyl, etc.), or R1 and R2 form, together with the adjacent carbon atom, a piperidine ring that is substituted with C1-6 alkyl (particularly, a C1-3 alkyl group such as methyl, etc.);
R3b is phenyl group that may be substituted with halogen (particularly, fluorine) or C1-6 alkyl (particularly, C1-3 alkyl such as methyl, ethyl, isopropyl, etc.);
R4 is (1) a C1-6 alkyl group (particularly, a C1-3 alkyl group such as methyl) that may be substituted with C6-14 aryl (particularly phenyl), thienyl, or pyridyl, which may be substituted with halogen (particularly, fluorine or chlorine), C1-6 alkoxy (particularly, a C1-3 alkoxy group such as methoxy), or C1-3 alkylenedioxy (particularly, methylenedioxy), or (2) a C6-14 arylcarbonyl group (particularly phenylcarbonyl group), a C7-16 aralkylcarbonyl group (particularly benzylcarbonyl group), a C6-14 arylsulfonyl group (particularly phenylsulfonyl group), nicotinoyl group, or thenoyl group, which may be substituted with halogen (particularly, fluorine or chlorine), C1-6 alkoxy (particularly, a C1-3 alkoxy group such as methoxy), or C1-3 alkylenedioxy (particularly, methylenedioxy);
R5 is hydrogen atom, a C1-6 alkyl group (particularly, a C1-3 alkyl group such as methyl), or C1-6 alkylcarbonyl (particularly, a C1-3 alkylcarbonyl group such as acetyl); and
ring C2 is benzene ring that may be further substituted with 1 to 3 C1-6 alkyl groups (particularly, a C1-3 alkyl group such as methyl), and the like are preferred and the compound wherein each of R1 and R2 is methyl;
R3b is phenyl group that may be substituted with fluorine, methyl, or isopropyl;
R4 is benzyl group or phenethyl group, which may be substituted with fluorine, methoxy, or methylenedioxy;
R5 is hydrogen atom or methyl group;
--- is a single bond; and
ring C2 is the benzene ring that is substituted with 3 methyl groups, and the like are particularly preferred.
Also, when --- indicates a double bond, R2 is not present and, as for R1, a C1-6 alkyl group that may be substituted is preferred and, particularly, a C1-3 alkyl group such as methyl or the like is preferred. As for other symbols, the same symbols as those described above are preferred. In particular, the compound wherein R3b is phenyl group that may be substituted with halogen (particularly, fluorine) or C1-6 alkyl (particularly, C1-3 alkyl such as methyl, ethyl, isopropyl, etc.); R4 is (1) a C1-6 alkyl group (particularly, a C1-3 alkyl group such as methyl) that may be substituted with C6-14 aryl (particularly phenyl), which may be substituted with halogen (particularly, fluorine) or C1-6 alkoxy (particularly, a C1-3 alkoxy group such as methoxy), or (2) a C6-14 arylcarbonyl group (particularly, phenylcarbonyl group) or a C7-16 aralkylcarbonyl group (particularly, benzylcarbonyl group), which may be substituted with halogen (particularly, fluorine) or C1-6 alkoxy (particularly, a C1-3 alkoxy group such as methoxy); R5 is hydrogen atom; and ring C2 is benzene ring that may be further substituted with 1 to 3 C1-6 alkyl groups (particularly, a C1-3 alkyl group such as methyl) are preferred.
As for specific examples of compound (Ib), the compounds produced in Example 1b to Example 67b described hereinafter, and the like are preferable, among which,
[1] N-(4-fluorobenzyl)-2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine (Example 4b) or a salt thereof,
[2] N-benzyl-3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine (Example 6b) or a salt thereof,
[3] 3-(4-isopropylphenyl)-N-(4-methoxybenzyl)-N,2,2,4,6,7-hexamethyl-2,3-dihydro-1-benzofuran-5-amine (Example 9b) or a salt thereof,
[4] 3-(4-isopropylphenyl)-N-[2-(4-methoxyphenyl)ethyl]-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine (Example 11b) or a salt thereof,
[5] N-(4-fluorobenzyl)-3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine (Example 19b) or a salt thereof,
[6] N-(1,3-benzodioxol-5-ylmethyl)-3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine (Example 23b) or a salt thereof,
[7] N-(4-fluorobenzyl)-3-(4-fluorophenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine (Example 31b) or a salt thereof,
[8] N-(4-methoxybenzyl)-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine (Example 33b) or a salt thereof,
[9] N-(4-fluorobenzyl)-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine (Example 35b) or a salt thereof,
[10] 3-(4-isopropylphenyl)-N-(4-methoxybenzyl)-2,4,6,7-tetramethyl-1-benzofuran-5-amine (Example 45b) or a salt thereof,
[11] N-(4-fluorobenzyl)-3-(4-isopropylphenyl)-2,4,6,7-tetramethyl-1-benzofuran-5-amine (Example 47b) or a salt thereof,
[12] N-(4-fluorobenzyl)-3-(4-fluorophenyl)-2,4,6,7-tetramethyl-1-benzofuran-5-amine (Example 51b) or a salt thereof,
[13] N-(4-fluorobenzyl)-3-(4-isopropylphenyl)-1xe2x80x2,4,6,7-tetramethylspiro[benzofuran-2(3H),4xe2x80x2-piperidine]-5-amine (Example 55b) or a salt thereof,
[14] (+)-N-(4-fluorobenzyl)-3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine, its hydrochloride (Example 61b), or other salts thereof, and the like are preferable and, particularly,
[1] N-(4-fluorobenzyl)-3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine (Example 19b) or a salt thereof,
[2] N-(4-fluorobenzyl)-3-(4-isopropylphenyl)-1xe2x80x2,4,6,7-tetramethylspiro[benzofuran-2(3H),4xe2x80x2-piperidine]-5-amine (Example 55b) or a salt thereof,
[3] (+)-N-(4-fluorobenzyl)-3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine hydrochloride (Example 61b), and the like are preferable.
The salts of the above-mentioned compounds may be exemplified by a metal salt, ammonium salt and a salt with an organic base in the case of having an acidic group such as xe2x80x94COOH or the like and by salts with an inorganic acid, an organic acid, a basic or acidic amino acid, and the like as well as inner salts in the case of having a bsic group such as xe2x80x94NH2 or the like. Preferred examples of a metal salt include alkali metal salts such as sodium salt, potassium salt, and the like; alkaline earth metal salts such as calcium salt, magnesium salt, barium salt, and the like; as well as aluminum salt, and so on. Preferred examples of a salt with an organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,Nxe2x80x2-dibenzylethylenediamine, and the like. Preferable examples of a salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Preferred examples of a salt with an organic acid include salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like. Preferred examples of a salt with a basic amino acid include salts with arginine, lysine, ornithine, and the like and preferable examples of a salt with an acidic amino acid include salts with aspartic acid, glutamic acid, and the like.
Among them, pharmaceutically acceptable salts are preferable. The examples thereof include inorganic salts such as alkali metal salts (sodium salt, potassium salt, and the like), alkaline earth metal salts (calcium salt, magnesium salt, barium salt, and the like) as well as ammonium salt, and so on in the case of having an acidic functional group in the compound and, also, include inorganic salts such as hydrochloride, sulfate, phosphate, hydrobromide, and the like or organic salts such as acetate, maleate, fumarate, succinate, methanesulfonate, p-toluenesulfonate, citrate, tartarate, and so on in the case of having a basic functional group in the compound.
Next, processes for production of compound (Ia) and compound (Iaxe2x80x2) of the present invention are illustrated.
Compound (Iaxe2x80x2) can be produced according to the processes for production of compound (Ia) as well as per se known processes such as the processes described in WO 95/29907, JP 5-194466 A, U.S. Pat. No. 4,881,967, U.S. Pat. No. 4,212,865, Tetrahedron Letters, Vol. 37, No. 51, pp. 9183-9186 (1996), and so on or modified processes thereof.
Compound (Ia) can be produced according to the following processes or modified processes thereof.
Each symbol in the compounds shown in the following reaction Schemes is as defined above. The compounds in the following reaction Schemes include the salts thereof and said salts are the same as those exemplified with respect to the salts of compound (Ia). 
Compound (Ia) is produced by reacting compound (IIa) with compound (IIIa) represented by the formula: 
(wherein, each of L1 and L2 indicates a leaving group and ring A is defined above), if necessary, in the presence of a base.
As for xe2x80x9csubstituent(s) that may be had, in addition to xe2x80x94NH2xe2x80x9d, by ring C1 in compound (IIa), the same number and the same substituent(s) as those xe2x80x9csubstituents that may be further hadxe2x80x9d, by ring C1 in compound (Ia) is used.
xe2x80x9cA leaving groupxe2x80x9d indicated by L1 and L2 is exemplified by hydroxyl, a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), C1-5 alkylsulfonyloxy that may be halogenated (for example, methanesulfonyloxy, ethanesulfonyloxy, trichloromethanesulfonyloxy, etc.), C6-10 arylsulfonyloxy that may be substitued, and the like. xe2x80x9cC6-10 arylsulfonyloxy that may be substituetedxe2x80x9d is exemplified by C6-10 arylsulfonyloxy (for example, phenylsulfonyloxy, naphthylsulfonyloxy, etc.) that may have 1 to 3 substituents, which are selected from C1-6 alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, or the like), C1-6 alkoxy (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.), and nitro, and so on. Specific examples include benzenesulfonyloxy, m-nitrobenzenesulfonyloxy, p-toluenesulfonyloxy, and the like.
Compound (IIIa) is a compound that is capable of forming, together with the amino group substituted on ring C1 of compound (IIa), a group represented by the formula: 
(wherein each symbol is as defined above), and, for example, there is used a compound represented by the formula: 
(wherein D1 indicates a group represented by formula xe2x80x94(CH2)d1xe2x80x94 (d1 indicates an integer of 0 to 3), which may be substituted with a hydrocarbon group that may be have halogen or a substituent, E1 indicates a group represented by formula xe2x80x94(CH2)e1xe2x80x94 (e1 indicates an integer of 0 to 3), which may be substituted with a hydrocarbon group that may have halogen or a substituent, the sum of d1 and e1 is an integer of 2 to 4, and each of L1 and L2 is as defined above) or the like.
As for said hydrocarbon group that may have halogen or a substituent, there is used the same group as the hydrocarbon group that may have halogen or a substituent, which is mentioned above as the substituent of a 5- to 7-membered nitrogen-containing heterocyclic ring indicated by ring B.
The amount of compound (IIIa) to be used is about 1.0 to about 5.0 moles, preferably about 1.0 to about 2.0 moles for 1 mole of compound (IIa).
Said xe2x80x9cbasexe2x80x9d is exemplified by a basic salt such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, or the like, an aromatic amine such as pyridine, lutidine, or the like, a tertiary amine such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, or the like, an alkali metal hydride such as sodium hydride, potassium hydride, or the like, a metal amide such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, or the like, a metal alkoxide such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, or the like, or the like.
The amount of the base to be used is about 1.0 to about 5.0 moles, preferably about 1.0 to about 3.0 moles for 1 mole of compound (IIa). Also, if desired, the reaction can also be carried out in the presence of a quaternary ammonium salt together with the base.
Said xe2x80x9cquaternary ammonium saltxe2x80x9d is exemplified by tetrabutylammonium iodide and the like.
The amount of the quaternary ammonium salt to be used is about 0.1 to about 2.0 moles, preferably about 0.5 to about 1.0 moles, for 1 mole of compound (IIa).
It is advantageous to carry out this reaction by using of a solvent inert to the reaction. Such a solvent, though being not particularly limited as far as the reaction proceeds, is preferably exemplified by alcohols such as methanol, ethanol, propanol, etc., ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc., a hydrocarbon such as benzene, toluene, cyclohexane, hexane, etc., amides such as N,N-dimethylformamide, N,N-dimethylacetamide, etc., halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc., nitrites such as acetonitrile, propionitrile, etc., sulfoxides such as dimethyl sulfoxide, etc., and a mixed solvent thereof, and the like.
The reaction time is usually about 30 minutes to about 48 hours, preferably for about 1 to about 24 hours. The reaction temperature is usually about xe2x88x9220 to about 200xc2x0 C., preferably about 0 to about 150xc2x0 C.
Alternatively, in place of the above-mentioned reaction, Mitsunobu reaction (Synthesis, 1981, pp. 1-27) can be employed.
Said reaction is carried out by reacting compound (IIa) with compound (IIIa), wherein each of L1 and L2 is OH, in the presence of azodicarboxylate (e.g., diethyl azodicarboxylate, etc.) and phosphine (e.g., triphenylphosphine, tributylphosphine, etc.).
The amount of the compound (IIIa) to be used, wherein each of L1 and L2 is OH, is about 1.0 to about 5.0 moles, preferably about 1.0 to about 2.0 moles, for 1 mole of compound (IIa).
The amount of each of said xe2x80x9cazodicarboxylatexe2x80x9d and xe2x80x9cphosphinexe2x80x9d to be used is respectively about 1.0 to about 5.0 moles, preferably about 1.0 to about 2.0 moles, for 1 mole of compound (IIa).
It is advantageous to carry out this reaction by using a solvent inert to the reaction. Such a solvent, though being not particularly limited as far as the reaction proceeds, is preferably exemplified by ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and the like, hydrocarbons such as benzene, toluene, cyclohexane, hexane, and the like, amides such as N,N-dimethylformamide, N,N-dimethylacetamide, and the like, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, and the like, nitriles such as acetonitrile, propionitrile, and the like, sulfoxides such as dimethyl sulfoxide and the like, or a mixed solvent thereof or the like.
The reaction time is usually about 5 minutes to about 48 hours, preferably for about 30 minutes to about 24 hours. The reaction temperature is usually about xe2x88x9220 to about 200xc2x0 C., preferably about 0 to about 100xc2x0 C.
Compound (IIa) can be produced according to per se known processes such as the processes described in JP 5-140142 A and so on or modified processes thereof.
In the case where compound (IIa) is a dihydrobenzofuran, the production is carried out according to the process described in the following reaction Scheme 
In the above formulas, Lxe2x80x2 indicates a leaving group and R8 indicates hydrogen atom or a group, in which a methylene is removed from R1.
xe2x80x9cA leaving groupxe2x80x9d indicated by Lxe2x80x2 is exemplified by hydroxyl, a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.), C1-6 alkylsulfonyloxy (e.g., methanesulfonyloxy, ethanesulfonyloxy, etc.), C6-10 arylsulfonyloxy that may be substituted, or the like.
xe2x80x9cA C6-10 arylsulfonyloxy that may be substitutedxe2x80x9d is exemplified by C6-10 arylsulfonyloxy (for example, phenylsulfonyloxy, naphthylsulfonyloxy, etc.) that may have 1 to 3 substituents, which are selected from C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), C1-6 alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.), and nitro, and so on. Specific examples include benzenesulfonyloxy, m-nitrobenzenesulfonyloxy, p-toluenesulfonyloxy, and the like
Compound (IVa) and compound (Va) are easily commercially available or are produced according to per se known methods.
Compound (VIa) is produced by reacting a phenolate anion, which is formed by treatment of compound (IVa) with a base, with compound (Va) represented by formula R8xe2x80x94CHLxe2x80x2xe2x80x94CHR2xe2x95x90CHR3a.
The amount of compound (Va) to be used is about 1.0 to about 5.0 moles, preferably about 1.0 to about 2.0 moles, for 1 mole of compound (IVa).
Said xe2x80x9cbasexe2x80x9d is exemplified by an inorganic base such as an alkali metal hydroxide exemplified by sodium hydroxide, potassium hydroxide, or the like, an alkali metal alkoxide such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, or the like, an alkali metal hydride such as sodium hydride, potassium hydride, or the like, a metal amide such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, or the like, a basic salt such as potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium acetate, or the like, or the like. The amount of the base to be used is about 0.5 to about 5.0 moles, preferably about 1.0 to about 3.0 moles, for 1 mole of compound (IVa).
It is advantageous to carry out this reaction by using a solvent inert to the reaction. Such a solvent is preferably exemplified by alcohols such as methanol, ethanol, propanol, or the like, hydrocarbons such as cyclohexane, hexane, benzene, toluene, xylene, and the like, ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether, and the like, amides such as N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide, and the like, sulfoxides such as dimethyl sulfoxide and the like, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like, water, and a mixed solvent thereof and the like.
The reaction time is usually about 10 minutes to about 8 hours, preferably for about 30 minutes to about 3 hours. The reaction temperature is usually about 0 to about 120xc2x0 C., preferably about 25 to about 100xc2x0 C.
The product can be isolated from the reaction mixture by using a known isolation means and can be easily purified according to a usual separation means (e.g., recrystallization, distillation, chromatography, etc.).
Compound (VIIa) is produced by Claisen rearrangement of compound (VIa).
It is advantageous to carry out the present reaction without using a solvent or by using a solvent inert to the reaction. Such a solvent to be used, though being not particularly limited as far as the reaction proceeds, is exemplified by alcohols such as methanol, ethanol, propanol, and the like, hydrocarbons such as cyclohexane, hexane, benzene, toluene, xylene, mesitylene, and the like, organic acids such as formic acid, acetic acid, and the like, ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether, and the like, anilines such as N,N-dimethylaniline, N,N-diethylaniline, and the like, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, and the like, and a mixed solvent thereof, and the like.
Also, if desired, this reaction may be carried out by using an acid catalyst. As for the acid catalyst, a Lewis acid such as aluminum chloride, boron trifluoride, or the like is used.
The amount of the acid catalyst to be used is, for instance, in the case of a Lewis acid, usually about 0.1 to about 20 moles, preferably about 0.1 to about 5.0 moles, for 1 mole of compound (VIa). The reaction time is usually about 30 minutes to about 24 hours, prefer ably for about 1 hour to about 6 hours. The reaction temperature is usually about xe2x88x9270 to about 300xc2x0 C., preferably about 150 to about 250xc2x0 C.
The product can be employed for the next reaction as the reaction mixture or a crude product, but the product can be isolated from the reaction mixture according to a conventional method and can be easily purified according to a usual separation means (e.g., recrystallization, distillation, chromatography, etc.).
Compound (IIa) can be produced by cyclization of compound (VIIa) with an acid catalyst.
The acid catalyst is exemplified by a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, or the like, a sulfonic acid such as p-toluenesulfonic acid, camphorsulfonic acid, or the like, a Lewis acid such as aluminum chloride, boron trifluoride, or the like or the like.
The amount of the acid catalyst to be used is, for example, in the case of a mineral acid, usually about 1 to about 100 moles, preferably about 10 to about 50 moles, for 1 mole of compound (VIIa) and, for instance, in the case of a sulfonic acid, usually about 0.1 to about 20 moles, preferably about 0.1 to about 5 moles, for 1 mole of compound (VIIa).
It is advantageous to carry out this reaction without using any solvent or by using a solvent inert to the reaction. Such a solvent is not particularly limited as far as the reaction proceeds. For example, in the case where a mineral acid is used, the solvent is preferably exemplified by a mixed solvent of water and an organic solvent such as an alcohol such as methanol, ethanol, propanol, or the like, a saturated hydrocarbon such as cyclohexane, hexane, or the like, an aromatic hydrocarbon such as benzene, toluene, xylene, or the like, an ether such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether, or the like, an amide such as N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide, or the like, a sulfoxide such as dimethyl sulfoxide or the like, a halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, or the like or water.
The reaction time is usually about 30 minutes to about 24 hours, preferably for about 1 hour to about 6 hours. The reaction temperature is usually about xe2x88x9278 to about 200xc2x0 C., preferably about xe2x88x9220 to about 150xc2x0 C.
The product can be employed for the next reaction as the reaction mixture or a crude product, but the product can be isolated from the reaction mixture according to a conventional method and can be easily purified according to a usual separation means (e.g., recrystallization, distillation, chromatography, etc.).
Also, in the case where compound (IIa) is a benzofuran, the production is carried out according to the process described in the following reaction Scheme. 
In the above formulas, hal indicates a halogen atom (for example, fluorine, chlorine, bromine, iodine, or the like).
Compound (IXa) is produced by reacting compound (VIIIa), which is synthesized according to the same manner as that for compound (VIIa), with a halogenating reagent.
Examples of xe2x80x9ca halogenating reagentxe2x80x9d include halogen atoms such as bromine, chlorine, iodine, or the like, imides such as N-bromosuccinimide or the like, halogen adducts such as benzyltrimethylammonium iodide chloride, benzyltrimethylammonium tribromide, or the like.
The amount of the halogenating reagent to be used is about 1.0 to about 5.0 moles, preferably about 1.0 to about 2.0 moles, for 1 mole of compound (VIIIa).
It is advantageous to carry out this reaction by using a solvent inert to the reaction. Such a solvent, though being not particularly limited as far as the reaction proceeds, is preferably exemplified by alcohols such as methanol, ethanol, propanol, and the like, hydrocarbons such as benzene, toluene, cyclohexane, hexane, and the like, amides such as N,N-dimethylformamide, N,N-dimethylacetamide, and the like, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, and the like, nitrites such as acetonitrile, propionitrile, and the like, sulfoxides such as dimethyl sulfoxide and the like, organic acids such as acetic acid, propionic acid, and the like, nitroalkanes such as nitromethane, and the like, aromatic amines such as pyridine, lutidine, quinoline, and the like, and a mixed solvent thereof and the like.
If desired, this reaction is carried out in the presence of a base or a radical initiator or under irradiation with a light.
Said xe2x80x9cbasexe2x80x9d is exemplified by a basic salt such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium acetate, potassium acetate, or the like, an aromatic amine such as pyridine, lutidine, or the like, a tertiary amine such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, or the like, or the like. The amount of the base to be used is about 0.8 to about 10 moles for 1 mole of compound (VIIIa).
xe2x80x9cA radical initiatorxe2x80x9d is exemplified by benzoyl peroxide, azobisisobutyronitrile, or the like.
The amount of the radical initiator to be used is about 0.01 to about 1.0 mole for 1 mole of compound (VIIIa).
In the case of irradiation with a light, a halogen lamp or the like can be used.
The reaction temperature is usually about xe2x88x9250 to about 150xc2x0 C., preferably about 0 to about 100xc2x0 C. The reaction time is usually about 5 minutes to about 24 hours, preferably for about 10 minutes to about 12 hours.
The product can be employed for the next reaction as the reaction mixture or a crude product, but the product can be isolated from the reaction mixture according to a conventional method and can be easily purified according to the usual separation means (e.g., recrystallization, distillation, chromatography, etc.).
Compound (IIa) is produced by treating compound (IXa) with a base.
Said xe2x80x9cbasexe2x80x9d is exemplified by an inorganic salt such as a metal hydroxide such as sodium hydroxide, potassium hydroxide, or the like, an organic amine such as triethylamine, 1.8-diazabicyclo[5,4,0]-7-undecene, pyridine, or the like, a metal alkoxide such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, or the like, an alkali metal hydride such as sodium hydride, potassium hydride, or the like, a metal amide such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, or the like, a basic salt such as potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium acetate, or the like, or the like.
The amount of the base to be used is about 0.5 to about 10 moles, preferably about 1.0 to about 5.0 moles, for 1 mole of compound (IXa).
It is advantageous to carry out the present reaction by the use of a solvent inert to the reaction. Such a solvent is preferably exemplified by alcohols such as methanol, ethanol, propanol, and the like, hydrocarbons such as cyclohexane, hexane, benzene, toluene, xylene, and the like, ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether, and the like, amides such as N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide, and the like, sulfoxides such as dimethyl sulfoxide and the like, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, and the like, water, and a mixed solvent thereof and the like.
The reaction time is usually about 10 minutes to about 24 hours, preferably for about 30 minutes to about 12 hours. The reaction temperature is usually about 0 to about 120xc2x0 C., preferably about 25 to about 100xc2x0 C.
The product can be employed for the next reaction as the reaction mixture or a crude product, but the product can be isolated from the reaction mixture according to a conventional method and can be easily purified according to a usual separation means (e.g., recrystallization, distillation, chromatography, etc.).
Compound (IIIa) is easily commercially available or is produced according to the well-known methods.
Also, compound (Ia) is produced according to the process described in the following reaction Scheme 4. 
In the above formulas, each of L3 and L4 indicates a leaving group.
xe2x80x9cA leaving groupxe2x80x9d indicated by L3 and L4 is exemplified by hydroxyl, a halogen atom (for example, fluorine, chlorine, bromine, iodine, or the like), C1-6 alkylsulfonyloxy (for example, methanesulfonyloxy, ethanesulfonyloxy, or the like), C6-10 arylsulfonyloxy that may have substituents, and the like.
xe2x80x9cA C6-10 arylsulfonyloxy that may have substituentsxe2x80x9d is exemplified by C6-10 arylsulfonyloxy (for example, phenylsulfonyloxy, naphthylsulfonyloxy, or the like) that may have 1 to 3 substituents selected from C1-6 alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, or the like), C1-6 alkoxy (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, or the like), and nitro, and so on. Specific examples include benzenesulfonyloxy, m-nitrobenzenesulfonyloxy, p-toluenesulfonyloxy, and the like.
Compound (Xa) is a compound that is capable of forming, together with the amino group substituted on ring C1 of compound (IIa), a group represented by the formula: 
wherein each symbol is as defined above, and, for example, there is used a compound represented by the formula: 
(wherein D2 indicates a group represented by formula xe2x80x94(CH2)d2xe2x80x94 (d2 is an integer of 0 to 2), which may be substituted with a hydrocarbon group that may have halogen or a substituent, E2 indicates a group represented by formula xe2x80x94(CH2)e2xe2x80x94 (e2 is an integer of 0 to 2), which may be substituted with a hydrocarbon group that may have halogen or substituent, the sum of d2 and e2 indicates an integer of 0 to 2, and each of L3 and L4 is as defined above), or the like.
As for said hydrocarbon group that may have halogen or a substituent, there is used the same group as the hydrocarbon group that may have a halogen or a substituent, which is mentioned above as the substituent of a 5- to 7-membered nitrogen-containing heterocyclic ring indicated by ring B.
Compound (Xa) and compound (XIa) are easily commercially available or are produced according to per se known methods.
Compound (XIIa) is obtained by reaction of compound (Xa) and compound (IIa), if necessary, in the presence of a base.
The amount of compound (Xa) to be used is about 1.0 to about 5.0 moles, preferably about 1.0 to about 2.0 moles, for 1 mole of compound (IIa).
Said xe2x80x9cbasexe2x80x9d is exemplified by a basic salt such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, or the like, an aromatic amine such as pyridine, lutidine, or the like, a tertiary amine such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, or the like, an alkali metal hydride such as sodium hydride, potassium hydride, or the like, a metal amide such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, or the like, a metal alkoxide such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, or the like, or the like. The amount of the base to be used is about 2.0 to about 5.0 moles, preferably about 2.0 to about 3.0 moles, for 1 mole of compound (IIa).
It is advantageous to carry out this reaction by using a solvent inert to the reaction. Such a solvent is preferably exemplified by alcohols such as methanol, ethanol, propanol, and the like, hydrocarbons such as cyclohexane, hexane, benzene, toluene, xylene, and the like, ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether, and the is like, amides such as N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide, and the like, sulfoxides such as dimethyl sulfoxide and the like, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, and the like, and a mixed solvent thereof and the like.
The reaction time is usually about 10 minutes to about 8 hours, preferably for about 30 minutes to about 3 hours. The reaction temperature is usually about 0 to about 120xc2x0 C., preferably about 25 to about 100xc2x0 C.
The product can be employed for the next reaction as the reaction mixture or a crude product, but the product can be isolated from the reaction mixture according to a conventional method and can be easily purified according to a usual separation means (e.g., recrystallization, distillation, chromatography, etc.).
In place of the above-mentioned reaction, compound (IIa) and compound (Xa) can be reacted in the presence of an appropriate condensing agent.
The amount of compound (Xa) to be used is about 1.0 to about 5.0 moles, preferably about 1.0 to about 2.0 moles, for 1 mole of compound (IIa).
As for said xe2x80x9ccondensing agentxe2x80x9d, there is used, for example, an N,Nxe2x80x2-dicarbodiimide such as N,Nxe2x80x2-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimetylaminopropyl)carbodiimide (WSC) hydrochloride, or the like, an azolite such as N,Nxe2x80x2-carbonyldiimidazole or the like, a dehydrating agent such as N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, phosphorus oxychloride, acetic anhydride, or the like, a 2-halopyridinium salt such as 2-chloromethylpyridinium iodide, 2-fluoro-1-chloromethylpyridinium iodide, or the like, or the like.
The amount of the condensing agent to be used is about 1.0 to about 5.0 moles, preferably about 2.0 to about 3.0 moles, for 1 mole of compound (IIa).
Also, if desired, the reaction may be carried out in the presence of a base together with the condensing agent. Said xe2x80x9cbasexe2x80x9d is exemplified by a basic salt such as potassium acetate, sodium acetate, or the like, 1-hydroxy-1H-benzotriazole (HOBT) monohydrate, or the like. The amount of the base to be used is about 1.0 to about 5.0 moles, preferably about 2.0 to about 3.0 moles, for 1 mole of compound (IIa).
It is advantageous to carry out this reaction by the use of a solvent inert to the reaction. Such a solvent is preferably exemplified by alcohols such as methanol, ethanol, propanol, and the like, hydrocarbons such as cyclohexane, hexane, benzene, toluene, xylene, and the like, ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether, and the like, amides such as N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide, and the like, sulfoxides such as dimethyl sulfoxide and the like, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, and the like, acid anhydrides such as acetic anhydride, and the like, and a mixed solvent thereof, and the like.
The reaction time is usually about 30 minutes to about 48 hours, preferably for about 30 minutes to about 24 hours. The reaction temperature is usually about 0 to about 120xc2x0 C., preferably about 25 to about 100xc2x0 C.
The product can be employed for the next reaction as the reaction mixture or a crude product, but the product can be isolated from the reaction mixture according to a conventional method and can be easily purified according to the usual separation means (e.g., recrystallization, distillation, chromatography, etc.).
Compound (XIIa) is synthesized also by a process comprising reacting compound (XIa) with compound (IIa), followed by, if desired, cyclization in the presence of a base.
The amount of compound (XIa) to be used is about 1.0 to about 5.0 moles, preferably about 1.0 to about 2.0 moles, for 1 mole of compound (IIa).
As for said xe2x80x9ccondensing agentxe2x80x9d, there is used, for example, an N,Nxe2x80x2-dicarbodiimide such as N,Nxe2x80x2-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimetylaminopropyl)carbodiimide (WSC) hydrochloride, or the like, an azolite such as N,Nxe2x80x2-carbonyldiimidazole or the like, a dehydrating agent such as N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, phosphorus oxychloride, acetic anhydride, or the like, a 2-halopyridinium salt such as 2-chloromethylpyridinium iodide, 2-fluoro-1-chloromethylpyridinium iodide, or the like, or the like.
The amount of the condensing agent to be used is respectively about 1.0 to about 5.0 moles, preferably about 1.0 to about 3.0 moles, for 1 mole of compound (IIa).
Also, if desired, the reaction may be carried out in the presence of a base together with the condensing agent. Said xe2x80x9cbasexe2x80x9d is exemplified by a basic salt such as potassium acetate, sodium acetate, or the like, 1-hydroxy-1H-benzotriazole (HOBT) monohydrate, or the like. The amount of the base to be used is about 1.0 to about 5.0 moles, preferably about 1.0 to about 3.0 moles, for 1 mole of compound (IIa).
It is advantageous to carry out this reaction by using a solvent inert to the reaction. Such a solvent is preferably exemplified by alcohols such as methanol, ethanol, propanol, and the like, hydrocarbons such as cyclohexane, hexane, benzene, toluene, xylene, and the like, ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether, and the like, amides such as N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide, and the like, sulfoxides such as dimethyl sulfoxide and the like, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, and the like, acid anhydrides such as acetic anhydride, and the like, and a mixed solvent thereof, and the like.
The reaction time is usually about 30 minutes to about 48 hours, preferably for about 30 minutes to about 24 hours. The reaction temperature is usually about 0 to about 120xc2x0 C., preferably about 25 to about 100xc2x0 C.
The product can be employed for the next reaction as the reaction mixture or a crude product, but the product can be isolated from the reaction mixture according to a conventional method and can be easily purified according to the usual separation means (e.g., recrystallization, distillation, chromatography, etc.).
Compound (Ia) is produced by reduction of compound (XIIa) with a reducing agent.
As for said xe2x80x9creducing agentxe2x80x9d, for example, a metal hydride such as sodium borohydride, lithium aluminum hydride, or the like, a borane such as a borane-tetrahydrofuran complex, or the like.
The amount of the reducing agent to be used is respectively about 0.5 to about 10 moles, preferably about 1.0 to about 5.0 moles, for 1 mole of compound (XIIa).
Also, if desired, an acid catalyst may be added together with the reducing agent. As for said xe2x80x9cacid catalystxe2x80x9d, a Lewis acid such as boron trifluoride, aluminum chloride, or the like or the like is used. The amount of said xe2x80x9cacid catalystxe2x80x9d to be used is respectively about 0.5 to about 10 moles, preferably about 1.0 to about 5.0 moles, for 1 mole of compound (XIIa).
It is advantageous to carry out this reaction without using any solvent or by using a solvent inert to the reaction. Such a solvent, though not particularly limited as far as the reaction proceeds, is preferably exemplified by alcohols such as methanol, ethanol, propanol, and the like, hydrocarbons such as cyclohexane, hexane, benzene, toluene, xylene, methylene, and the like, organic acids such as formic acid, acetic acid, and the like, ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether, and the like, anilines such as N,N-dimethylaniline, N,N-diethylaniline, and the like, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, and the like, and a mixed solvent thereof, and the like.
The reaction time is usually about 10 minutes to about 24 hours, preferably for about 30 minutes to about 12 hours. The reaction temperature is usually about 0 to about 120xc2x0 C., preferably about 25 to about 100xc2x0 C.
The product can be employed for the next reaction as the reaction mixture or a crude product, but the product can be isolated from the reaction mixture according to a conventional method and can be easily purified according to a usual separation means (e.g., recrystallization, distillation, chromatography, and the like).
Also, in the case where compound (IIa) is a dihydrobenzofuran, the production is carried out according to the process described in the following reaction Scheme 5. 
Compound (XIIIa) is produced by subjecting compound (IVa) to the addition reaction of a protective group that has been generally employed in the peptide chemistry, etc.
As for the protective group (P) for amino group, there is used, for example, formyl, or C1-6 alkyl-carbonyl (for example, acetyl, propionyl, or the like), phenylcarbonyl, C1-6 alkoxy-carbonyl (for example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, or the like), phenyloxycarbonyl, C7-10 aralkyloxy-carbonyl (for example, benzyloxycarbonyl or the like), trityl, phthaloyl, or the like, which respectively may be substituted. As for the substituent thereof, a halogen atom (for example, fluorine, chlorine, bromine, iodine, or the like), C1-6 alkyl-carbonyl (for example, acetyl, propionyl, valeryl, or the like), nitro, or the like is used. The number of the substituents is 1 to 3.
As for the protective group (Pxe2x80x2) for hydroxyl group, there is used, for example, C1-6 alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, or the like), phenyl, C7-1. aralkyl (for example, benzyl or the like), formyl, C1-6 alkyl-carbonyl (for example, acetyl, propionyl, or the like), phenyloxycarbonyl, C7-11, aralkyloxy-carbonyl (for example, benzyloxycarbonyl or the like), tetrahydropyranyl, tetrahydrofuranyl, silyl, or the like, which respectively may be substituted. As for the substituent thereof, for example, a halogen atom (for example, fluorine, chlorine, bromine, iodine, or the like), C1-6 alkyl (for example, methyl, ethyl, tert-butyl, or the like), C7-11 aralkyl (for example, benzyl or the like), C6-10 aryl (for example, phenyl, naphthyl, or the like), nitro, or the like is used. The number of the substituents is 1 to 4.
Compound (XIVa) is produced by reaction of compound (XIIIa) and a brominating reagent.
As for xe2x80x9ca brominating reagentxe2x80x9d, bromine, an imide such as N-bromosuccinimide or the like, a halogen adduct such as benzyltrimethylammonium tribromide, or the like or the like. The amount of the brominating reagent to be used is about 1.0 to about 5.0 moles, preferably about 1.0 to about 2.0 moles, for 1 mole of compound (XIIIa).
It is advantageous to carry out this reaction by using a solvent inert to the reaction. Such a solvent, though being not particularly limited as far as the reaction proceeds, is preferably exemplified by ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and the like, alcohols such as methanol, ethanol, propanol, and the like, hydrocarbons such as benzene, toluene, cyclohexane, hexane, and the like, amides such as N,N-dimethylformamide, N,N-dimethylacetamide, and the like, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, and the like, nitrites such as acetonitrile, propionitrile, and the like, sulfoxides such as dimethyl sulfoxide and the like, organic acids such as acetic acid, propionic acid, and the like, nitroalkanes such as nitromethane, and the like, aromatic amines such as pyridine, lutidine, quinoline, and the like, and a mixed solvent thereof and the like.
If desired, this reaction is carried out in the presence of a base or a Lewis acid or an iron.
Said xe2x80x9cbasexe2x80x9d is exemplified by a basic salt such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium acetate, potassium acetate, or the like, an aromatic amine such as pyridine, lutidine, or the like, a tertiary amine such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, or the like. The amount of the base to be used is about 0.8 to about 10 moles for 1 mole of compound (XIIIa).
As for xe2x80x9ca Lewis acidxe2x80x9d, for example, ferric chloride, aluminum chloride, boron trifluoride, or the like is exemplified. The amount of the Lewis acid to be used is about 0.01 to about 1 mole for 1 mole of compound (XIIIa).
As for xe2x80x9can ironxe2x80x9d, the amount of the iron to be used is about 0.01 to about 1 mole for 1 mole of compound (XIIIa).
The reaction temperature is usually about xe2x88x9250 to about 150xc2x0 C., preferably about 0 to about 100xc2x0 C. The reaction time is usually about 5 minutes to about 24 hours, preferably for about 10 minutes to about 12 hours.
The product can be employed for the next reaction as the reaction mixture or a crude product, but the product can be isolated from the reaction mixture according to a conventional method and can be easily purified according to the usual separation means (e.g., recrystallization, distillation, chromatography, etc.).
Compound (XVIa) is produced by lithiation of compound (XIVa), followed by reaction with a ketone (XVa).
As for xe2x80x9ca lithiating reagentxe2x80x9d, an alkyl lithium such as n-butyllithium is used. The amount of the lithiating reagent to be used is about 1.0 to about 5.0 moles, preferably about 1.0 to about 3.0 moles, for 1 mole of compound (XIVa).
It is advantageous to carry out this reaction by using a solvent inert to the reaction. Such a solvent, though being not particularly limited as far as the reaction proceeds, is preferably exemplified by ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and the like, hydrocarbons such as benzene, toluene, cyclohexane, hexane, and the like, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, and the like, and a mixed solvent thereof and the like.
The reaction temperature is usually about xe2x88x9278 to about 100xc2x0 C., preferably about xe2x88x9278 to about 50xc2x0 C. The reaction time is usually about 5 minutes to about 24 hours, preferably for about 10 minutes to about 3 hours.
The product can be employed for the next reaction as the reaction mixture or a crude product, but the product can be isolated from the reaction mixture according to a conventional method and can be easily purified according to the usual separation means (e.g., recrystallization, distillation, chromatography, etc.).
Compound (IIa) is produced by deprotection and cyclization of compound (XVIa) with an acid catalyst. As for the acid catalyst, there is used a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, or the like, a sulfonic acid such as p-toluenesulfonic acid, camphorsulfonic acid, or the like, a Lewis acid such as aluminum chloride, boron trifluoride, or the like or the like. The amount of the acid catalyst to be used is, for instance, in the case of a mineral acid, usually about 1 to about 100 moles, preferably about 10 to about 50 moles, for 1 mole of compound (XVIa) and, for instance, in the case of a sulfonic acid, usually about 0.1 to about 20 moles, preferably about 0.1 to about 5 moles, for 1 mole of compound (XVIa).
It is advantageous to carry out this reaction without using any solvent or by using a solvent inert to the reaction. Such a solvent is not particularly limited as far as the reaction proceeds. For example, in the case where a mineral acid is used, the solvent is preferably exemplified by a mixed solvent of water and an organic solvent such as an alcohol such as methanol, ethanol, propanol, or the like, a saturated hydrocarbon such as cyclohexane, hexane, or the like, an aromatic hydrocarbon such as benzene, toluene, xylene, or the like, an ether such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether, or the like, an amide such as N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide, or the like, a sulfoxide such as dimethyl sulfoxide or the like, a halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, or the like or water.
The reaction time is usually about 30 minutes to about 24 hours, preferably for about 30 minutes to about 6 hours. The reaction temperature is usually about xe2x88x9278 to about 200xc2x0 C., preferably about xe2x88x9220 to about 150xc2x0 C.
The product can be employed for the next reaction as the reaction mixture or a crude product, but the product can be isolated from the reaction mixture according to a conventional method and can be easily purified according to the usual separation means (e.g., recrystallization, distillation, chromatography, etc.).
The starting compound for the above-mentioned compound (Ia) may form a salt, which, though not being particularly limited as far as the reaction is achieved, is exemplified by the same salt as that of the above-mentioned compound (Ia) may form, or the like.
The configurational isomers (E and Z forms) of compound (Ia) can be isolated and purified, at the moment when the isomerization occurs, according to a conventional separation means such as extraction, recrystallization, distillation, chromatography, and the like, thereby being able to isolate and purify the compound. Also, according to the methods described in Shin Jikken Kagaku Kouza (Text books on New Experimental Chemistry) 14 [Edited by Nihon Kagaku Kai (Chemical Society of Japan)], page 251 to page 253 and in Jikken Kagaku Kouza (Text books on Experimental Chemistry), 4th Edition, 19 [Edited by Nihon Kagaku Kai (Chemical Society of Japan)], page 273 to page 274, and modified methods thereof, the isomerization of the double bond is allowed to proceed by the use of heating, an acid catalyst, a transition-metal complex, a metal catalyst, a radical-species catalyst, irradiation with a light, a strong basic catalyst, or the like, thereby being able to obtain the corresponding pure isomers.
Compound (Ia) forms stereoisomers depending on a particular kind of a substituent. Both isomers, which present alone or as a mixture thereof, are included in the present invention.
Compound (Ia) and compound (Iaxe2x80x2) may be in the form of hydrates or non-hydrates.
In each case, compound (Ia) can be synthesized, as desired further, by deprotection reaction, acylation reaction, alkylation reaction, hydrogenation reaction, oxidation reaction, reduction reaction, carbon-chain elongation reaction, and substituent-replacement reaction, each of which is carried out alone or in a combination of two or more of them.
In the case where the title compound is obtained in a free state according to the above-mentioned reaction, the a compound may be converted into a salt according to a conventional method, or in the case where the compound is obtained as a salt, it can be converted into a free form or another salt according to a conventional method. The thus-obtained compound (Ia) can be isolated from the reaction mixture and purified according to a known means such as trans-solubilization, concentration, solvent extraction, fractional distillation, crystallization, recrystallization, chromatography, or the like.
In the case where compound (Ia) exists as configurational isomers, diastereomers, conformers, or the like, each of them can be isolated, as desired, by the above-mentioned separation and purification means. Also, in the case where compound (Ia) is in racemic forms, they can be separated into the d form and the 1 form by a conventional optical resolution means.
Also, in the case where a functional group such as amino group, hydroxyl group, carboxyl group or the like is present in each of the above-mentioned reactions, the reaction may be carried out after introduction of a protective group that is generally employed in the peptide chemistry or the like and the title compound can be obtained by removing the protective group, as needed, after the reaction.
As for the protective group, there is used, for ago example, formyl or a C1-6 alkylcarbonyl (for example, acetyl, propionyl, or the like), phenylcarbonyl, a C1-6 alkoxycarbonyl (for example, methoxycarbonyl, ethoxycarbonyl, or the like), phenoxycarbonyl, a C7-10 aralkyloxycarbonyl (for example, benzyloxycarbonyl or the like), trityl, phthaloyl, or the like, which respectively may have substituents. As for the substituent thereof, a halogen atom (for example, fluorine, chlorine, bromine, iodine, or the like), a C1-6 alkylcarbonyl (for example, acetyl, propionyl, valeryl, or the like), nitro, or the like is used. The number of the substituents is approximately 1 to 3.
Also, as for the method for removing the protective group, per se known methods or modified methods thereof are employed. For example, there is employed treatment with an acid, a base, a ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate or the like, or a reduction reaction.
Next, processes for production of compounds (Ib) of the present invention are illustrated.
Compounds (Ib) can be produced according to the following processes or modified processes thereof. 
Compound (Ib) is produced by reaction of compound (IIb) and compound (IIIb) represented by formula R4xe2x80x94L, wherein L indicates a leaving group and R4 is as defined above.
xe2x80x9cA leaving groupxe2x80x9d indicated by L is exemplified by hydroxyl, a halogen atom (for example, fluorine, chlorine, bromine, iodine, or the like), C1-5, alkylsulfonyloxy that may be halogenated (for example, methanesulfonyloxy, ethanesulfonyloxy, trichloromethanesulfonyloxy, or the like), C6-10 arylsulfonyloxy that may be substituted, or the like.
xe2x80x9cA C6-10 arylsulfonyloxy that may be substitutedxe2x80x9d is exemplified by C6-10 arylsulfonyloxy (for example, phenylsulfonyloxy, naphthylsulfonyloxy, or the like) that may have 1 to 3 substituents selected from C1-6 alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, or the like), C1-6 alkoxy (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, or the like), and nitro, and so on. Specific examples include benzenesulfonyloxy, m-nitrobenzenesulfonyloxy, p-toluenesulfonyloxy, and the like.
(1) In the following are described the reaction conditions in the case where R4 is xe2x80x9can acyl group containing an aromatic group that may be substitutedxe2x80x9d.
The reaction of compound (IIb) and compound (IIIb) is carried out, if desired, in the presence of a base or an acid.
The amount of compound (IIIb) to be used is about 1.0 to about 5.0 moles, preferably about 1.0 to about 2.0 moles, for 1 mole of compound (IIb).
Said xe2x80x9cbasexe2x80x9d is exemplified by a basic salt such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, or the like, an aromatic amine such as pyridine, lutidine, or the like, a tertiary amine such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, or the like, an alkali metal hydride such as sodium hydride, potassium hydride, or the like, a metal amide such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, or the like, a metal alkoxide such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, or the like, or the like.
Said xe2x80x9cacidxe2x80x9d is exemplified by a sulfonic acid such as methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, or the like, a Lewis acid such as zinc chloride, aluminum chloride, or the like, or the like.
The amount of said xe2x80x9cbasexe2x80x9d to be used is about 0.1 to about 10 moles, preferably about 0.8 to about 2 moles, for 1 mole of compound (IIb).
The amount of said xe2x80x9cacidxe2x80x9d to be used is about 0.1 to about 10 moles, preferably about 0.8 to about 3 moles, for 1 mole of compound (IIb).
It is advantageous to carry out this reaction without using any solvent or by using a solvent inert to the reaction. Such a solvent, though being not particularly limited as far as the reaction proceeds, is preferably exemplified by a solvent such as an ether such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, or the like, a hydrocarbon such as benzene, toluene, cyclohexane, hexane, or the like, an amide such as N,N-dimethylformamide, N,N-dimethylacetamide, or the like, a halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, or the like, a nitrile such as acetonitrile, propionitrile, or the like, a sulfoxide such as dimethyl sulfoxide or the like, a nitrogen-containing, aromatic amine such as pyridine, lutidine, quinoline, or the like, or a mixed solvent thereof or the like. The reaction temperature is usually about xe2x88x9220 to about 150xc2x0 C., preferably about 0 to about 100xc2x0 C. The reaction time is usually about 5 minutes to about 24 hours, preferably for about 10 minutes to about 5 hours.
In place of the above-mentioned reaction, compound (IIb) and compound (IIIb) can be reacted in the presence of an appropriate condensing agent.
The amount of compound (IIIb) to be used is about 1.0 to about 5.0 moles, preferably about 1.0 to about 2.0 moles, for 1 mole of compound (IIb).
As for a condensing agent, there is used, for example, an N,Nxe2x80x2-dicarbodiimide such as N,Nxe2x80x2-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimetylaminopropyl)carbodiimide (WSC) hydrochloride, or the like, an azolite such as N,Nxe2x80x2-carbonyldiimidazole or the like, a dehydrating agent such as N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, phosphorus oxychloride, or the like, a 2-halopyridinium salt such as 2-chloromethylpyridinium iodide, 2-fluoro-1-chloromethylpyridinium iodide, or the like, or the like.
The amount of the condensing agent to be used is about 1.0 to about 5.0 moles, preferably about 1.0 to about 2.0 moles, for 1 mole of compound (IIb).
It is advantageous to carry out this reaction by using a solvent inert to the reaction. Such a solvent, though being not particularly limited as far as the reaction proceeds, is preferably exemplified by a solvent such as an ether such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, or the like, a hydrocarbon such as benzene, toluene, cyclohexane, hexane, or the like, an amide such as N,N-dimethylformamide, N,N-dimethylacetamide, or the like, a halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, or the like, a nitrile such as acetonitrile, propionitrile, or the like, a sulfoxide such as dimethyl sulfoxide or the like, or a mixed solvent thereof or the like.
The reaction time is usually about 5 minutes to about 48 hours, preferably for about 30 minutes to about 24 hours. The reaction temperature is usually about xe2x88x9220 to about 200xc2x0 C., preferably about 0 to about 100xc2x0 C.
(2) In the following are described the reaction conditions in the case where R4 is xe2x80x9can aliphatic hydrocarbon group that may have an optionally substituted aromatic group, which may be further substitutedxe2x80x9d.
The reaction of compound (IIb) and compound (IIIb) represented by R4xe2x80x94L is carried out, if desired, in the presence of a base.
The amount of compound (IIIb) to be used is about 1.0 to about 5.0 moles, preferably about 1.0 to about 2.0 moles, for 1 mole of compound (IIb).
Said xe2x80x9cbasexe2x80x9d is exemplified by a basic salt such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, or the like, an aromatic amine such as pyridine, lutidine, or the like, a tertiary amine such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, or the like, an alkali metal hydride such as sodium hydride, potassium hydride, or the like, a metal amide such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, or the like, a metal alkoxide such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, or the like, or the like.
The amount of the base to be used is about 1.0 to about 5.0 moles, preferably about 1.0 to about 2.0 moles, for 1 mole of compound (IIb).
It is advantageous to carry out this reaction by the use of a solvent inert to the reaction. Such a solvent, though being not particularly limited as far as the reaction proceeds, is preferably exemplified by a solvent such as an alcohol such as methanol, ethanol, propanol, or the like, an ether such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, or the like, a hydrocarbon such as benzene, toluene, cyclohexane, hexane, or the like, an amide such as N,N-dimethylformamide, N,N-dimethylacetamide, or the like, a halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, or the like, a nitrile such as acetonitrile, propionitrile, or the like, a sulfoxide such as dimethyl sulfoxide or the like, or a mixed solvent thereof or the like.
The reaction time is usually about 30 minutes to about 48 hours, preferably for about 1 hour to about 24 hours. The reaction temperature is usually about xe2x88x9220 to about 200xc2x0 C., preferably about 0 to about 150xc2x0 C.
In place of the above-mentioned reaction, compound (Ib) can also be synthesized by reductive amination. 
Compound (Ib) is produced by condensation of compound (IIb) and compound (IVb) represented by formula R9xe2x80x94CHO (R9 indicates a group where a methylene is removed from R4.), followed by reduction with a reducing agent.
The amount of compound (IVb) to be used is about 1.0 to about 5.0 moles, preferably about 1.0 to about 2.0 moles, for 1 mole of compound (IIb).
As for said xe2x80x9creducing agentxe2x80x9d, for example, a metal hydride such as sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, or the like, a borane such as a borane-tetrahydrofuran complex or the like, a hydrosilane such as triethylsilane or the like, formic acid, or the like is used. Also, as desired, an acid catalyst may be added together with the reducing agent.
The acid catalyst is exemplified by a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, or the like, a sulfonic acid such as methanesulfonic acid, is p-toluenesulfonic acid, or the like, an organic acid such as acetic acid, propionic acid, trifluoroacetic acid, or the like, a Lewis acid such as zinc chloride, aluminum chloride, or the like, or the like.
The amount of said xe2x80x9creducing agentxe2x80x9d to be used is about 0.25 to about 5.0 moles, preferably about 0.5 to about 2.0 moles, for 1 mole of compound (IIb).
The amount of the acid catalyst to be used is, for instance, in the case of a mineral acid, usually about 1 to about 100 moles, preferably about 1 to about 20 moles, for 1 mole of compound (IIb).
It is advantageous to carry out this reaction by using a solvent inert to the reaction. Such a solvent, though being not particularly limited as far as the reaction proceeds, is preferably exemplified by a solvent such as an alcohol such as methanol, ethanol, propanol, or the like, an ether such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, or the like, a hydrocarbon such as benzene, toluene, cyclohexane, hexane, or the like, an amide such as N,N-dimethylformamide, N,N-dimethylacetamide, or the like, or a mixed solvent thereof or the like.
The reaction time is usually about 5 minutes to about 48 hours, preferably for about 30 minutes to about 24 hours. The reaction temperature is usually about xe2x88x9220 to about 200xc2x0 C., preferably about 0 to about 100xc2x0 C.
In said reaction, after condensation of compound (IIb) with compound (IVb), the reduction with a reducing agent is replaced by catalytic hydrogenation reaction in the presence of a variety of a catalyst under hydrogen atmosphere to carry out the production. The catalyst to be employed is exemplified by platinum oxide, platinum on activated carbon, palladium on activated carbon, nickel, copper-chrome oxide, rhodium, cobalt, ruthenium, or the like. The usage amount of the catalyst is about 5 to about 1000% by weight, preferably about 5 to about 1000% by weight, for compound (IIb).
It is advantageous to carry out the present reaction by the use of a solvent inert to the reaction. Such a solvent, though being not particularly limited as far as the reaction proceeds, is preferably exemplified by a solvent such as an alcohol such as methanol, ethanol, propanol, or the like, an ether such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, or the like, a hydrocarbon such as benzene, toluene, cyclohexane, hexane, or the like, an amide such as N,N-dimethylformamide, N,N-dimethylacetamide, or the like, water, or the like, or a mixed solvent thereof or the like.
The reaction time is usually about 30 minutes to about 48 hours, preferably for about 30 minutes to about 24 hours. The reaction temperature is usually about 0 to about 120xc2x0 C., preferably about 20 to about 80xc2x0 C.
In place of the above-mentioned reaction, there can be employed a method to reduce the acylamide derivative that is synthesized in the above-mentioned (1).
As for the reducing agent, for example, a metal hydride such as sodium borohydride, lithium aluminum hydride, or the like, a borane such as a borane-tetrahydrofuran complex or the like, or the like is used.
Also, if desired, an acid catalyst may be added together with the reducing agent. The acid catalyst to be used is exemplified by a Lewis acid such as a trifluoroborane-diethyl ether complex, aluminum chloride, or the like, or the like.
The amount of said reducing agent to be used is respectively about 0.25 to about 10 moles, preferably about 0.5 to about 5 moles, for 1 mole of the acylamide derivative.
The amount of said Lewis acid to be used is respectively about 0.25 to about 10 moles, preferably about 0.5 to about 5 moles, for 1 mole of the acylamide derivative.
It is advantageous to carry out this reaction by using a solvent inert to the reaction. Such a solvent, though being not particularly limited as far as the reaction proceeds, is preferably exemplified by a solvent such as an alcohol such as methanol, ethanol, propanol, or the like, an ether such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, or the like, a hydrocarbon such as benzene, toluene, cyclohexane, hexane, or the like, water or the like, or a mixed solvent thereof or the like.
The reaction time is usually about 30 minutes to about 24 hours, preferably for about 1 hour to about 16 hours. The reaction temperature is usually about 0 to about 150xc2x0 C., preferably about 20 to about 100xc2x0 C.
The product (Ib) obtained as shown above can be isolated from the reaction mixture according to the known isolation means and can be easily purified according to the separation means such as recrystallization, distillation, chromatography, and the like.
Compound (Ib) can be produced, for example, according to the process described in JP 5-140142 A or a modified process thereof.
In the case where compound (IIb) is a dihydrobenzofuran (compound (IIbxe2x80x2)), the production is carried out according to the method described in the following reaction Scheme. 
In the above formulas, Lxe2x80x2 indicates a leaving group and R9 indicates the hydrogen atom or a group, in which a methylene is removed from R1.
xe2x80x9cA leaving groupxe2x80x9d indicated by Lxe2x80x2 is exemplified by hydroxyl, a halogen atom (for example, fluorine, chlorine, bromine, iodine, or the like), a C1-6 alkylsulfonyloxy (for example, methylsulfonyloxy, ethylsulfonyloxy, or the like), a C6-10. arylsulfonyloxy that may be substituted, or the like.
xe2x80x9cA C6-10 arylsulfonyloxy that may be substitutedxe2x80x9d is exemplified by a C6-10 arylsulfonyloxy (for example, phenylsulfonyloxy, naphthylsulfonyloxy, or the like) that may have 1 to 3 substituents, which are selected from a C6-10 alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, or the like), a C1-6 alkoxy (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, or the like), and nitro, and so on, where specific examples include benzenesulfonyloxy, m-nitrobenzenesulfonyloxy, p-toluenesulfonyloxy, and the like.
Compound (Vb) and compound (VIb) are easily commercially available or are produced according to the well-known methods.
Compound (VIIb) is produced by reaction of a phenolate anion, which is formed by treatment of compound (Vb) with a base, and compound (VIb) represented by formula R9xe2x80x94CHLxe2x80x2xe2x80x94CHR2xe2x95x90CHR3b.
The amount of compound (VIb) to be used is about 1.0 to about 5.0 moles, preferably about 1.0 to about 2.0 moles, for 1 mole of compound (Vb).
xe2x80x9cA basexe2x80x9d is exemplified by an inorganic base such as an alkali metal hydroxide exemplified by sodium hydroxide, potassium hydroxide, or the like, an alkali metal alkoxide such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, or the like, an alkali metal hydride such as sodium hydride, potassium hydride, or the like, a metal amide such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, or the like, a basic salt such as potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium acetate, or the like, or the like. The usage amount of the base is about 0.5 to about 5.0 moles, preferably about 1.0 to about 3.0 moles, for 1 mole of compound (Vb).
It is advantageous to carry out this reaction by using a solvent inert to the reaction. Such a solvent is preferably exemplified by an alcohol such as methanol, ethanol, propanol, or the like, a hydrocarbon such as cyclohexane, hexane, benzene, toluene, xylene, or the like, an ether such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether, or the like, an amide such as N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide, or the like, a sulfoxide such as dimethyl sulfoxide or the like, a halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, or the like, water, or a mixed solvent thereof or the like.
The reaction time is usually about 10 minutes to about 8 hours, preferably for about 30 minutes to about 3 hours. The reaction temperature is usually about 0 to about 120xc2x0 C., preferably about 25 to about 100xc2x0 C.
The product can be employed for the next reaction as the reaction mixture or a crude product, but the product can be isolated from the reaction mixture according to a conventional method and can be easily purified according to the usual separation means (e.g., recrystallization, distillation, chromatography, etc.).
Compound (VIIIb) is produced by the Claisen rearrangement reaction of compound (VIIb).
It is advantageous to carry out this reaction without using a solvent or by using a solvent inert to the reaction. Such a solvent to be used, though being not particularly limited as far as the reaction proceeds, is exemplified by an alcohol such as methanol, ethanol, propanol, or the like, a hydrocarbon such as cyclohexane, hexane, benzene, toluene, xylene, methylene, or the like, an organic acid such as formic acid, acetic acid, or the like, an ether such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether, or the like, an aniline such as N,N-dimethylaniline, N,N-diethylaniline, or the like, a halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, or the like, or a mixed solvent thereof or the like.
Also, if desired, this reaction may be carried out by using an acid catalyst. As for the acid catalyst, for example, a Lewis acid such as aluminum chloride, boron trifluoride, or the like or the like is used. The usage amount of the acid catalyst is, for instance, in the case of a Lewis acid, usually about 0.1 to about 20 moles, preferably about 0.1 to about 5.0 moles, for 1 mole of compound (VIIb). The reaction time is usually about 30 minutes to about 24 hours, preferably for about 1 hour to about 6 hours. The reaction temperature is usually about xe2x88x9270 to about 300xc2x0 C., preferably about 150 to about 250xc2x0 C.
The product can be employed for the next reaction as the reaction mixture or a crude product, but the product can be isolated from the reaction mixture according to a conventional method and can be easily purified according to the usual separation means (e.g., recrystallization, distillation, chromatography, etc.).
Compound (IIbxe2x80x2) is produced by cyclization of compound (VIIIb) with an acid catalyst. The acid catalyst is exemplified by a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, or the like, a sulfonic acid such as p-toluenesulfonic acid, camphorsulfonic acid, or the like, a Lewis acid such as aluminum chloride, boron trifluoride, or the like or the like. The amount of the acid catalyst to be used is, for instance, in the case of a mineral acid, usually about 1 to about 100 moles, preferably about 10 to about 50 moles, for 1 mole of compound (VIIIb) and, for instance, in the case of a sulfonic acid, usually about 0.1 to about 20 moles, preferably about 0.1 to about 5 moles, for 1 mole of compound (VIIIb).
It is advantageous to carry out this reaction without using any solvent or by using a solvent inert to the reaction. Such a solvent is not particularly limited as far as the reaction proceeds. For instance, in the case where a mineral acid is used, the solvent is preferably exemplified by a mixed solvent of water and an organic solvent such as an alcohol such as methanol, ethanol, propanol, or the like, a saturated hydrocarbon such as cyclohexane, hexane, or the like, an aromatic hydrocarbon such as benzene, toluene, xylene, or the like, an ether such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether, or the like, an amide such as N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide, or the like, a sulfoxide such as dimethyl sulfoxide or the like, a halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, or the like or water.
The reaction time is usually about 30 minutes to about 24 hours, preferably for about 30 minutes to about 6 hours. The reaction temperature is usually about xe2x88x9278 to about 200xc2x0 C., preferably about xe2x88x9220 to about 150xc2x0 C.
The product can be employed for the next reaction as the reaction mixture or a crude product, but the product can be isolated from the reaction mixture according to a conventional method and can be easily purified according to the usual separation means (e.g., recrystallization, distillation, chromatography, etc.).
Also, in the case where compound (IIb) is a benzofuran (compound (IIbxe2x80x3)), the production is carried out according to the method described in the following reaction Scheme. 
In the above formulas, hal indicates a halogen atom (for example, fluorine, chlorine, bromine, iodine, or the like).
Compound (Xb) is produced by reaction of compound (IXb), which is synthesized in a manner similar to the case for compound (VIIIb), and a halogenating reagent.
As for xe2x80x9ca halogenating reagentxe2x80x9d, for example, a halogen such as bromine, chlorine, iodine, or the like, an imide such as N-bromosuccinimide or the like, a halogen adduct such as benzyltrimethylammonium iodide chloride, benzyltrimethylammonium tribromide, or the like or the like. The usage amount of the halogenating reagent is about 1.0 to about 5.0 moles, preferably about 1.0 to about 2.0 moles, for 1 mole of compound (IXb).
It is advantageous to carry out this reaction by the use of a solvent inert to the reaction. Such a solvent, though being not particularly limited as far as the reaction proceeds, is preferably exemplified by an alcohol such as methanol, ethanol, propanol, or the like, a hydrocarbon such as benzene, toluene, cyclohexane, hexane, or the like, an amide such as N,N-dimethylformamide, N,N-dimethylacetamide, or the like, a halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, or the like, a nitrile such as acetonitrile, propionitrile, or the like, a sulfoxide such as dimethyl sulfoxide or the like, an organic acid such as acetic acid, propionic acid, or the like, a nitroalkane such as nitromethane, or the like, an aromatic amine such as pyridine, lutidine, quinoline, or the like, or a mixed solvent thereof or the like.
If desired, this reaction is carried out in the presence of a base or a radical initiator or under irradiation with a light.
A xe2x80x9cbasexe2x80x9d is exemplified by a basic salt such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium acetate, potassium acetate, or the like, an aromatic amine such as pyridine, lutidine, or the like, a tertiary amine such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, or the like, or the like. The usage amount of the base is about 0.8 to about 10 moles for 1 mole of compound (IXb).
xe2x80x9cA radical initiatorxe2x80x9d is exemplified by benzoyl peroxide, azobisisobutyronitrile, or the like. The usage amount of the radical initiator is about 0.01 to about 1.0 mole for 1 mole of compound (IXb).
In the case of irradiation with a light, a halogen lamp or the like can be used.
The reaction temperature is usually about xe2x88x9250 to about 150xc2x0 C., preferably about 0 to about 100xc2x0 C. The reaction time is usually about 5 minutes to about 24 hours, preferably for about 10 minutes to about 12 hours.
The product can be employed for the next reaction as the reaction mixture or a crude product, but the product can be isolated from the reaction mixture according to a conventional method and can be easily purified according to the usual separation means (e.g., recrystallization, distillation, chromatography, etc.).
Compound (IIbxe2x80x3) is produced by treatment of compound (Xb) with a base. xe2x80x9cA basexe2x80x9d is exemplified by an inorganic salt such as a metal hydroxide such as sodium hydroxide, potassium hydroxide, or the like, an organic amine such as triethylamine, 1.8-diazabicyclo[5,4,0]-7-undecene, pyridine, or the like, a metal alkoxide such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, or the like, an alkali metal hydride such as sodium hydride, potassium hydride, or the like, a metal amide such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, or the like, a basic salt such as potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium acetate, or the like, or the like.
The amount of the base to be used is about 0.5 to about 10 moles, preferably about 1.0 to about 5.0 moles, for 1 mole of compound (Xb).
It is advantageous to carry out this reaction by using a solvent inert to the reaction. Such a solvent is preferably exemplified by an alcohol such as methanol, ethanol, propanol, or the like, a hydrocarbon such as cyclohexane, hexane, benzene, toluene, xylene, or the like, an ether such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether, or the like, an amide such as N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide, or the like, a sulfoxide such as dimethyl sulfoxide or the like, a halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, or the like, water, or a mixed solvent thereof or the like.
The reaction time is usually about 10 minutes to about 24 hours, preferably for about 30 minutes to about 12 hours. The reaction temperature is usually about 0 to about 120xc2x0 C., preferably about 25 to about 100xc2x0 C.
The product can be employed for the next reaction as the reaction mixture or a crude product, but the product can be isolated from the reaction mixture according to a conventional method and can be easily purified according to the usual separation means (e.g., recrystallization, distillation, chromatography, etc.).
Also, in the case where compound (IIb) is a dihydrobenzofuran (compound (IIbxe2x80x2)), the production is carried out according to the method described in the following reaction Scheme. 
Compound (XIb) is produced by subjecting compound (Vb) to the addition reaction of a protective group that has been generally employed in the peptide chemistry.
As for the protective group (P) for amino group, there is used, for example, formyl or a C1-6 alkyl-carbonyl (for example, acetyl, propionyl, or the like), phenylcarbonyl, a C1-6 alkoxy-carbonyl (for example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, or the like), phenyloxycarbonyl, a C7-10 aralkyloxy-carbonyl (for example, benzyloxycarbonyl or the like), trityl, phthaloyl, or the like, which respectively may have substituents. As for the substituent thereof, a halogen atom (for example, fluorine, chlorine, bromine, iodine, or the like), a C1-6 alkyl-carbonyl (for example, acetyl, propionyl, valeryl, or the like), nitro, or the like is used, where the number of the substituents is 1 to 3.
As for the protective group (Pxe2x80x2) for hydroxyl group, there is used, for example, a C1-6 alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, or the like), phenyl, a C7-11 aralkyl (for example, benzyl or the like), formyl, a C1-6 alkyl-carbonyl (for example, acetyl, propionyl, or the like), phenyloxycarbonyl, a C7-11 aralkyloxy-carbonyl (for example, benzyloxycarbonyl or the like), tetrahydropyranyl, tetrahydrofuranyl, silyl, or the like, which respectively may have substituents. As for the substituent thereof, for example, a halogen atom (for example, fluorine, chlorine, bromine, iodine, or the like), a C1-6 alkyl (for example, methyl, ethyl, tert-butyl, or the like), a C7-11 aralkyl (for example, benzyl or the like), a C6-10 aryl (for example, phenyl, naphthyl, or the like), nitro, or the like is used, where the number of the substituents is 1 to 4.
Compound (XIIb) is produced by reaction of compound (XIb) and a brominating reagent.
As for xe2x80x9ca brominating reagentxe2x80x9d, bromine, an imide such as N-bromosuccinimide or the like, a halogen adduct such as benzyltrimethylammonium tribromide, or the like or the like. The usage amount of the brominating reagent is about 1.0 to about 5.0 moles, preferably about 1.0 to about 2.0 moles, for 1 mole of compound (XIb).
It is advantageous to carry out this reaction by the use of a solvent inert to the reaction. Such a solvent, though being not particularly limited as far as the reaction proceeds, is preferably exemplified by an ether such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, or the like, an alcohol such as methanol, ethanol, propanol, or the like, a hydrocarbon such as benzene, toluene, cyclohexane, hexane, or the like, an amide such as N,N-dimethylformamide, N,N-dimethylacetamide, or the like, a halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, or the like, a nitrile such as acetonitrile, propionitrile, or the like, a sulfoxide such as dimethyl sulfoxide or the like, an organic acid such as acetic acid, propionic acid, or the like, a nitroalkane such as nitromethane, or the like, an aromatic amine such as pyridine, lutidine, quinoline, or the like, or a mixed solvent thereof or the like.
If desired, this reaction is carried out in the presence of a base or a Lewis acid or an iron.
xe2x80x9cA basexe2x80x9d is exemplified by a basic salt such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, sodium acetate, potassium acetate, or the like, an aromatic amine such as pyridine, lutidine, or the like, a tertiary amine such as triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, or the like, or the like. The usage amount of the base is about 0.8 to about 10 moles for 1 mole of compound (XIb).
As for xe2x80x9ca Lewis acidxe2x80x9d, for example, ferric chloride, aluminum chloride, boron trifluoride, or the like is exemplified. The usage amount of the Lewis acid is about 0.01 to about 1 mole for 1 mole of compound (XIb).
As for xe2x80x9can ironxe2x80x9d, the usage amount of the iron is about 0.01 to about 1 mole for 1 mole of compound (XIb).
The reaction temperature is usually about xe2x88x9250 to about 150xc2x0 C., preferably about 0 to about 100xc2x0 C. The reaction time is usually about 5 minutes to about 24 hours, preferably for about 10 minutes to about 12 hours.
The product can be employed for the next reaction as the reaction mixture or a crude product, but the product can be isolated from the reaction mixture according to a conventional method and can be easily purified according to the usual separation means (e.g., recrystallization, distillation, chromatography, etc.).
Compound (XIVb) is produced by lithiation of compound (XIIb), followed by reaction with a ketone (XIIIb).
As for xe2x80x9ca lithiating reagentxe2x80x9d, an alkyl lithium such as n-butyllithium is used. The usage amount of the lithiating reagent is about 1.0 to about 5.0 moles, preferably about 1.0 to about 3.0 moles, for 1 mole of compound (XIIb).
It is advantageous to carry out this reaction by using a solvent inert to the reaction. Such a solvent, though being not particularly limited as far as the reaction proceeds, is preferably exemplified by an ether such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, or the like, a hydrocarbon such as benzene, toluene, cyclohexane, hexane, or the like, a halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, or the like, or a mixed solvent thereof or the like.
The reaction temperature is usually about xe2x88x9278 to about 100xc2x0 C., preferably about xe2x88x9278 to about 50xc2x0 C. The reaction time is usually about 5 minutes to about 24 hours, preferably for about 10 minutes to about 3 hours.
The product can be employed for the next reaction as the reaction mixture or a crude product, but the product can be isolated from the reaction mixture according to a conventional method and can be easily purified according to the usual separation means (e.g., recrystallization, distillation, chromatography, etc.).
Compound (IIbxe2x80x2) is produced by deprotection and cyclization of compound (XIVb) with an acid catalyst. As for the acid catalyst, there is used a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, or the like, a sulfonic acid such as p-toluenesulfonic acid, camphorsulfonic acid, or the like, a Lewis acid such as aluminum chloride, boron trifluoride, or the like or the like. The amount of the acid catalyst to be used is, for instance, in the case of a mineral acid, usually about 1 to about 100 moles, preferably about 10 to about 50 moles, for 1 mole of compound (XIVb) and, for instance, in the case of a sulfonic acid, usually about 0.1 to about 20 moles, preferably about 0.1 to about 5 moles, for 1 mole of compound (XIVb).
It is advantageous to carry out this reaction without using any solvent or by using a solvent inert to the reaction. Such a solvent is not particularly limited as far as the reaction proceeds. For example, in the case where a mineral acid is used, the solvent is preferably exemplified by a mixed solvent of water and an organic solvent such as an alcohol such as methanol, ethanol, propanol, or the like, a saturated hydrocarbon such as cyclohexane, hexane, or the like, an aromatic hydrocarbon such as benzene, toluene, xylene, or the like, an ether such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether, diisopropyl ether, or the like, an amide such as N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide, or the like, a sulfoxide such as dimethyl sulfoxide or the like, a halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, or the like or water.
The reaction time is usually about 30 minutes to about 24 hours, preferably for about 30 minutes to about 6 hours. The reaction temperature is usually about xe2x88x9278 to about 200xc2x0 C., preferably about xe2x88x9220 to about 150xc2x0 C.
The product can be employed for the next reaction as the reaction mixture or a crude product, but the product can be isolated from the reaction mixture according to a conventional method and can be easily purified according to the usual separation means (e.g., recrystallization, distillation, chromatography, etc.).
Also, in the case where a functional group such as amino group, hydroxyl group, carboxyl group or the like exists in each of the above-mentioned reactions, the reaction may be carried out after introduction of a protective group that is generally employed in the peptide chemistry or the like and the title compound can be obtained by removing the protective group, as needed, after the reaction.
As for the protective group, there is used, for example, formyl or a C1-6 alkyl-carbonyl (for example, acetyl, propionyl, or the like), phenylcarbonyl, a C1-6 alkoxy-carbonyl (for example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, or the like), phenoxycarbonyl, a C7-10 aralkyloxy-carbonyl (for example, benzyloxycarbonyl or the like), trityl, phthaloyl, or the like, which respectively may have substituents. As for the substituent thereof, a halogen atom (for example, fluorine, chlorine, bromine, iodine, or the like), a C1-6 alkyl-carbonyl (for example, acetyl, propionyl, valeryl, or the like), nitro, or the like is used, where the number of the substituents is approximately 1 to 3.
Also, as for the method for removing the protective group, the well-known methods or modified methods thereof are employed, where there is employed, for example, a method to treat with an acid, a base, a ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, or the like or the reduction reaction.
The starting compound for the above-mentioned compound (Ib) may form a salt, which, though not being particularly limited as far as the reaction is achieved, is exemplified by a salt similar to the salt that the above-mentioned compound (Ib) may form, or the like.
The configurational isomers (E and Z forms) of compound (Ib) can be isolated and purified, at the moment when the isomerization occurs, according to the usual separation means such as extraction, recrystallization, distillation, chromatography, and the like, thereby being able to produce pure compounds. Also, according to the methods described in Shin Jikken Kagaku Kouza (Text books on New Experimental Chemistry) 14 [Edited by Nihon Kagaku Kai (Chemical Society of Japan)], page 251 to page 253 and in Jikken Kagaku Kouza (Text books on Experimental Chemistry), 4th Edition, 19 [Edited by Nihon Kagaku Kai (Chemical Society of Japan)], page 273 to page 274, and modified methods thereof, the isomerization of the double bond is allowed to proceed by the use of heating, an acid catalyst, a transition-metal complex, a metal catalyst, a radical-species catalyst, irradiation with a light, a strong basic catalyst, or the like, thereby being able to obtain the corresponding pure isomers.
Compound (Ib) forms stereoisomers depending on a particular kind of the substituent, but the isomers, which present as a single form or as a mixture, are included in the present prevention.
Compound (Ib) may be in the form of hydrates or non-hydrates.
In each case, compound (Ib) can be synthesized, as desired further, by deprotection reaction, acylation reaction, alkylation reaction, hydrogenation reaction, oxidation reaction, reduction reaction, carbon-chain elongation reaction, and substituent-replacement reaction, each of which is carried out singly or in a combination of two or more of them.
In the case where the title compound is obtained in a free state according to the above-mentioned reaction, the compound may be converted into a salt according to a conventional method, or in the case where the compound is obtained as a salt, it can be converted into a free form or another salt according to a conventional method. The thus-obtained compound (Ib) can be isolated from the reaction solution and purified according to the well-known means such as trans-solubilization, concentration, solvent extraction, fractional distillation, crystallization, recrystallization, chromatography, and the like.
In the case where compound (Ib) exists as configurational isomers, diastereomers, conformers, or the like, each of them can be isolated, as desired, by the above-mentioned separation and purification means. Also, in the case where compound (Ib) is in racemic forms, they can be separated into the d form and the l form by usual optical resolution means.
A prodrug of compound (Ia), (Iaxe2x80x2), or (Ib) of the present invention may be a compound that is converted into compound (Ia) or the like by a reaction with an enzyme, gastric acid, or the like under a physiological condition in the living body, namely, a compound that is converted into compound (Ia) or the like by an enzymatic oxidation, reduction, hydrolysis, or the like or a compound that is converted into compound (Ia) or its salt by hydrolysis with gastric acid or the like.
Examples of the prodrug of compound (Ia) or the like include a compound, where the amino group in compound (I) or the like is acylated, alkylated, or phosphorylated (for example, a compound or the like, where the amino group in compound (I) or the like is converted into eicosanoylamino, alanylamino, benzylaminocarbonylamino, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methoxycarbonylamino, tetrahydrofuranylamino, pyrrolidylmethylamino, pivaloyloxymethylamino, or tert-butylamino); a compound, where the hydroxyl group in compound (Ia) or the like is acylated, alkylated, phosphorylated, or converted into the borate (for example, a compound or the like, where the hydroxyl group in compound (Ia) or the like is converted into acetyloxy, palmitoyloxy, propanoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy, or dimethylaminomethylcarbonyloxy); a compound or the like, where the carboxyl group in compound (Ia) or the like is esterified or amidated (for example, a compound or the like, where the carboxyl group is subjected to ethyl esterification, phenyl esterification, carboxyoxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl esterification, cyclohexyloxycarbonyl esterification, or conversion into the methyl amide), and so on. These compounds can be produced from compound (Ia) according to a well-known method.
Also, the prodrug of compound (Ia) or the like may be a compound that is converted into compound (Ia) or the like under a physiological condition as described in xe2x80x9cIyakuhin No Kaihatu (Development of Drugs)xe2x80x9d, Volume 7, Molecular Design, Hirokawa Shoten, published in 1990; page 163 to page 198.
Compound (Ia), (Iaxe2x80x2), or (Ib) or a salt thereof or a prodrug thereof (hereinafter, abbreviated as the compound of the present invention) possesses excellent pharmaceutical actions such as a neurotrophic factor-like action, an action to enhance the neurotrophic factor activity, an action to inhibit the nerve degeneration, an action to promote the neuroregeneration, an antioxidant action, an action to inhibit the nerve cell death by xcex2-amyloid and the like and also possesses excellent properties such as a low toxicity, a small side effect, and the like, thereby being useful as pharmaceuticals.
The compound of the present invention acts as a neurotrophic factor-like substance, a substance to enhance the neurotrophic factor activity, a substance to inhibit the neurodegeneration or a substance to inhibit the xcex2-amyloid toxicity for mammalian animals (for example, mouse, rat, hamster, rabbit, cat, dog, cattle, sheep, monkey, human, and the like), thereby inhibiting the nerve cell death and promoting the neuroregeneration. Also, the compound of the present invention possesses an action to activate the choline system (for examples, an action to enhance the activity of choline acetyltransferase and the like), thereby resulting in an increase of the content of acetylcholine, an activation of the neurological function, and the like.
Accordingly, the compound of the present invention is effective for the nerve degenerative diseases (for example, Alzheimer""s disease, Parkinson""s disease, amyotrophic lateral sclerosis (ALS), Huntington""s disease, spinocerebellar degeneration and the like), psychoneurotic diseases (for example, schizophrenia and the like), the head injury, the spinal cord injury, the cerebrovascular accident, the cerebrovascular dementia, the peripheral neuropathies (for examples, diabetic neuropathy and the like), and the like), thereby being employed as prophylactic/therapeutic drugs for these diseases.
The compound of the present invention has a low toxicity and is capable of being safely administered orally or parenterally (for examples, topical, rectal, or intravenous administration, and the like) as it is or as a pharmaceutical composition, which is produced by compounding with a pharmaceutically permissible carrier according to the well-known means, such as a tablet (includes a sugar-coated tablet, a film-coated tablet, an intraoral disintegrating tablet, or the like), a powder, a granule, a capsule (includes a soft capsule), a liquid and solution, an injection, a suppository, a sustained-release formulation, a plaster, or the like.
The content of the compound of the present invention in the preparation of the present invention is about 0.01 to about 100% by weight of the total weight of the preparation.
Said dosage differs depending on the administration object, the administration route, the disease, and the like, whereas, for instance, in the case where an oral preparation is administered to an adult as a therapeutic drug for the Alzheimer""s disease, the dosage as the active ingredient of the compound of the present invention is about 0.1 to about 20 mg/kg of body weight, preferably about 0.2 to about 10 mg/kg of body weight, more preferably about 0.5 to about 10 mg/kg of body weight, where the dosage can be administered with being divided in 1-3 times daily.
Furthermore, there may be used in combination with another active ingredient [for example, a choline esterase inhibitor (for example, Aricept (donepezil) or the like), a cerebral function activator (for example, idebenone, Vinpocetine, or the like), a therapeutic drug for the Parkinson""s disease (for example, L-dopa, deprenyl, or the like), a therapeutic drug for the amyotrophic lateral sclerosis (for example, riluzole or the like), a neurotrophic factor, or the like]. For the combined usage, said another active ingredient and the compound of the present invention or a salt thereof may be compounded according to the well-known method and then formulated into one pharmaceutical composition (for example, a tablet, a powder, a granule, a capsule (includes a soft capsule), a liquid and solution, an injection, a suppository, a sustained-release formulation, or the like) or each of them may be subjected to a separate formulation, followed by a simultaneous or time-lapse administration to the same object.
The pharmaceutically acceptable carrier, which may be used for the production of the preparation of the present invention, is exemplified by a variety of organic or inorganic carrier substances, which have been conventionally employed as formulation materials, such as, for example, a bulking agent, a lubricant, a binding agent, and a disintegrator in solid formulations; a vehicle, a solubilizing agent, a suspending agent, an isotonicity agent, a buffering agent, and an analgesic in liquid formulations; and the like. Also, as needed, usual excipients such as a preservative, an antioxidant, a coloring agent, a sweetening agent, an absorbing agent, a wetting agent, and the like can be used.
The bulking agent is exemplified by lactose, white soft sugar, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid, or the like.
The lubricant is exemplified by magnesium stearate, potassium stearate, talc, colloidal silica, or the like.
The binding agent is exemplified by crystalline cellulose, white soft sugar, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl pyrrolidone, starch, sucrose, gelatin, methyl cellulose, sodium carboxymethyl cellulose, or the like.
The disintegrator is exemplified by starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, L-hydroxypropyl cellulose, or the like.
The vehicle is exemplified by water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil, and the like.
The solubilizing agent is exemplified by polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisamiomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, or the like.
The suspending agent is exemplified by a surface active agent such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate, or the like; a hydrophilic, high molecular substance such as polyvinyl alcohol, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, or the like; etc.
The isotonicity agent is exemplified by glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol, or the like.
The buffering agent is exemplified by a buffer solution of a phosphate, an acetate, a carbonate, a citrate, or the like.
The analgesic is exemplified by benzyl alcohol or the like.
The preservative is exemplified by a paraoxybenzoic acid ester, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, or the like.
The antioxidant is exemplified by a sulfite, ascorbic acid, xcex1-tocopherol, or the like.
The present invention is further illustrate in detail by the following Reference Examples, Examples, Formulation Examples, and Experimental Examples, but these examples are merely examples, which are not intended to limit the present invention and may be varied without departing from the scope of the present invention.
xe2x80x9cRoom temperaturexe2x80x9d in the following Reference Examples and Examples usually indicates about 10 to about 35xc2x0 C. Unless otherwise stated, % indicates the percent by weight.
Other symbols used in the present text indicate the following meanings.
s: singlet
d: doublet
dd: doublet of doublets
dt: doublet of triplets
t: triplet
q: quartet
septet: septet
m: multiplet
br: broad
J: coupling constant
Hz: hertz
CDCl3: deuterated chloroform
DMSO-d6: deuterated dimethyl sulfoxide
1H-NMR: proton nuclear magnetic resonance
[Compounds (Ia)]